Rahul B. Ganatra, MD, MPH

Case Presentation: A 65-year-old male veteran presented to the Veterans Affairs Boston Healthcare System (VABHS) emergency department with progressive fatigue, dyspnea on exertion, lightheadedness, and falls over the last month. New bilateral lower extremity numbness up to his knees developed in the week prior to admission and prompted him to seek care. Additional history included 2 episodes of transient loss of consciousness resulting in falls and a week of diarrhea, which had resolved. His medical history was notable for hypothyroidism secondary to Hashimoto thyroiditis, seizure disorder, vitiligo, treated hepatitis C virus (HCV) infection, alcohol use disorder in remission, diabetes mellitus, posttraumatic stress disorder, and traumatic brain injury. His medications included levothyroxine and carbamazepine. He previously worked as a barber but recently had stopped due to cognitive impairment. On initial evaluation, the patient's vital signs included a temperature of 36.3 °C, heart rate of 77 beats per minute, blood pressure of 139/83 mm Hg, respiratory rate of 18 breaths per minute, and 99% oxygen saturation while breathing ambient air. Physical examination was notable for a frail-appearing man in no acute distress. His conjunctivae were pale, and cardiac auscultation revealed a normal heart rate and irregularly irregular heart rhythm. A neurologic examination revealed decreased vibratory sensation in both feet, delayed and minimal speech, and a blunted affect. His skin was warm and dry with patchy hypopigmentation across the face and forehead. Laboratory results are shown in the Table. Testing 2 years previously found the patient's hemoglobin to be 11.4 g/dL and serum creatinine to be 1.7 mg/dL. A peripheral blood smear showed anisocytosis, hypochromia, decreased platelets, ovalocytes, elliptocytes, and rare teardrop cells, with no schistocytes present. Chest radiography and computed tomography of the head were unremarkable. An abdominal ultrasound revealed a complex hypoechoic mass with peripheral rim vascularity in the right hepatic lobe measuring 3.9 cm × 3.6 cm × 3.9 cm.

Lindsey Ulin, MD, Chief Medical Resident, VABHS and Brigham and Women’s Hospital (BWH):

To build the initial differential diagnosis, we are joined today by 3 internal medicine residents who were not involved in the care of this patient. Dr. Hickey, Dr. Ross and Dr. Manivannan, how did you approach this case?

Meghan Hickey, MD, Senior Internal Medicine Resident, VABHS and Boston Medical Center (BMC):

The constellation of fatigue, weakness, blunted affect, and delayed, minimal speech suggested central nervous system involvement, which I sought to unify with hemolytic anemia and his liver mass. The first diagnosis I considered was Wilson disease; however, this genetic disorder of copper metabolism often presents with liver failure or cirrhosis in young or middle-aged women, so this presentation would be atypical. Next, given the hypopigmentation was reported only on sun-exposed areas of the patient’s face, I considered possibilities other than vitiligo to avoid diagnostic anchoring. One such alternate diagnosis is porphyria cutanea tarda (PCT), which presents in middle-aged and older adults with a photosensitive dermatitis that can include acute sensory deficits. Manifestations of PCT can be triggered by alcohol consumption, though his alcohol use disorder was thought to be in remission, as well as HCV, for which he previously received treatment. However, anemia is uncommon in PCT, so the patient’s low hemoglobin would not be explained by this diagnosis. Lastly, I considered thrombotic thrombocytopenic purpura (TTP) given his anemia, thrombocytopenia, and neurologic symptoms; however, the patient did not have fever or a clear inciting cause, his renal dysfunction was relatively mild, and the peripheral blood smear revealed no schistocytes, which should be present in TTP.

Caroline Ross, MD, and Alan Manivannan, MD; Senior Internal Medicine Residents, VABHS and BMC:

We noted several salient features in the history and physical examination. First, we sought to explain the bilateral lower extremity numbness and decreased vibratory sensation in the feet leading to falls. We also considered his anemia and thrombocytopenia with signs of hemolysis including elevated lactate dehydrogenase (LDH), low haptoglobin, and elevated total bilirubin; however, with normal coagulation parameters. These results initially raised our concern for a thrombotic microangiopathy (TMA) such as TTP. However, the peripheral smear lacked schistocytes, making this less likely. The combination of his neurologic symptoms and TMA-like laboratory findings but without schistocytes raised our concern for vitamin B12 deficiency. Vitamin B12 deficiency can cause a pseudo-TMA picture with laboratory finding similar to TTP; however, schistocytes are typically absent. We also considered the possibility of hepatocellular carcinoma (HCC) with bone marrow infiltration leading to anemia given the finding of a liver mass on his abdominal ultrasound and low reticulocyte index. However, this would not explain his hemolysis. We also considered chronic disseminated intravascular coagulation in the setting of a malignancy as a contributor, but again, the smear lacked schistocytes and his coagulation parameters were normal. Finally, we considered a primary bone marrow process such as myelodysplastic syndrome due to the bicytopenia with poor bone marrow response and smear with tear drop cells and elliptocytes. However, we felt this was less likely as this would not explain his hemolytic anemia.

Dr. Ulin:

To refine the differential diagnosis, we are joined by an expert clinician who was also not involved in the care of this patient to describe his approach to this case. Dr. Orlander, can you walk us through your clinical reasoning?

Jay Orlander, MD, MPH: Professor of Medicine, Section of General Internal Medicine, Boston University Chobanian & Avedisian School of Medicine, Associate Chief, Medical Service, VABHS:

I will first comment on the hepatic mass. The hypoechoic liver mass with peripheral vascularity suggests a growing tumor. The patient has a history of substance use disorder with alcohol and treated HCV. He remains at increased risk for HCC even after prior successful HCV treatment and has 2 of 4 known risk factors for developing HCC— diabetes mellitus and alcohol use—the other 2 being underlying metabolic dysfunctionassociated steatotic liver disease (MASLD) and the presence of hepatic fibrosis, which we have not yet assessed. Worsening liver function can lead to cognitive issues and alcohol to peripheral neuropathy, but his story is not consistent with this. For his liver mass, I recommend a nonurgent magnetic resonance image for further evaluation.

Next, let’s consider his markedly elevated thyrotropin (TSH). Cognitive impairment along with lethargy, fatigue, and decreased exercise tolerance can be prominent features in severe hypothyroidism, but this diagnosis would not explain his hematologic findings.¹

I view the principal finding of his laboratory testing as being that his bone marrow is failing to maintain adequate blood elements. He has a markedly low hematocrit along with low platelets and low-normal white blood cell counts. There is an absence of schistocytes on the blood smear, and after correcting his reticulocyte count for his degree of anemia (observed reticulocyte percentage [0.8%] x observed hematocrit [15.3%] / expected hematocrit [40%]), results in a reticulocyte index of 0.12, which is low. This suggests his bone marrow is failing to manufacture red blood cells at an appropriate rate. His haptoglobin is unmeasurable, so there is some free heme circulating. Hence, I infer that hemolysis and ineffective erythropoiesis are both occurring within the bone marrow, which also explains the slight elevation in bilirubin.

Intramedullary hemolysis with a markedly elevated LDH can be seen in severe vitamin B₁₂ deficiency, which has many causes, but one cause in particular warrants consideration in this case: pernicious anemia. Pernicious anemia has an overall prevalence of about 0.1%, but is more common in older adults, and is estimated to be present in 2% to 3% of adults aged > 65 years.² Prevalence is also increased in patients with other autoimmune diseases such as vitiligo and hypothyroidism, which our patient has.³ The pathophysiology of pernicious anemia relates to either autoimmune gastric parietal cell destruction and/or the development of antibodies against intrinsic factor, which is required for absorption of vitamin B₁₂. Early disease may present with macrocytosis and a normal hemoglobin initially, but anemia develops over time if left untreated. When the primary cause of pernicious anemia is gastric parietal cell destruction, there is also an associated lack of stomach acid production (achlorhydria) with resulting poor micronutrient absorption; specifically, vitamin D, vitamin C, and iron. Hence, 30% of patients diagnosed with pernicious anemia have concurrent iron deficiency, which may counteract macrocytosis and result in a normal mean corpuscular volume. 4 Some medications are also poorly absorbed in achlorhydric states, such as levothyroxine, and treatment doses need to be increased, which could explain his markedly elevated TSH despite presumed medication adherence.

Vitamin B₁₂ is essential for both the peripheral and central nervous systems. Longstanding severe B₁₂ deficiency can explain all of his neurological and neurocognitive changes. The most common neurologic findings in B₁₂ deficiency are symmetric paresthesias or numbness and gait problems. The sensory neuropathy affects the lower extremities more commonly than the upper. Untreated, patients can develop progressive weakness, ataxia, and orthostatic hypotension with syncope, as well as neuropsychiatric changes including depression or mood impairment, cognitive slowing, forgetfulness, and dementia.

Dr. Ulin:

Dr. Orlander, which pieces of objective data are most important in forming your differential diagnosis, and what tests would you obtain next?

Dr. Orlander:

The 3 most salient laboratory tests to me are a complete blood count, with all cell lines impacted but the hemoglobin and hematocrit most dramatically impacted, reticulocyte count of 0.8%, which is inappropriately low and hence suggests a hypoproliferative anemia, and the elevated LDH > 5000 IU/L.

Since my suspected diagnosis is pernicious anemia, I would obtain a blood smear looking for hypersegmented neutrophils, > 1 white blood cells with 5 lobes, or 1 with 6 lobes, which should clinch the diagnosis. Methylmalonic acid (MMA) levels are the most sensitive test for B₁₂ deficiency, so I would also obtain that. Finally, I would check a B₁₂ level, since in a patient with pernicious anemia, I would expect the level to be < 200 pg/mL.

Dr. Ulin:

Before we reveal the results of the patient’s additional workup, how do you approach interpreting B₁₂ levels?

Dr. Orlander:

Measuring B12 can sometimes be problematic: the normal range is considered 200 to 900 pg/mL, but patients with measured low-normal levels in the range of 200 to 400 pg/mL can actually be physiologically deficient. There are also several common causes of falsely low and falsely high B₁₂ levels in the absence of B₁₂ deficiency. Hence, for patients with mild symptoms that could be due to B₁₂ deficiency, many clinicians choose to just treat with B₁₂ supplementation, deeming it safer to treat than miss an early diagnosis. B₁₂ is involved in hydrogen transfer to convert MMA into succinyl-CoA and hence true vitamin B₁₂ deficiency causes an increase in MMA.

Decreased production of vitamin B12 binding proteins, like haptocorrin, has been proposed as the mechanism for spurious low values.⁵ Certain conditions or medications can also cause spurious low serum vitamin B₁₂ levels and thus might cause the appearance of vitamin B₁₂ deficiency when the patient is not deficient. Examples include multiple myeloma, HIV infection, pregnancy, oral contraceptives, and phenytoin use. An example of spuriously low vitamin B₁₂ level in pregnancy was demonstrated in a series of 50 pregnant individuals with low vitamin B₁₂ levels (45-199 pg/mL), in whom metabolite testing for MMA and homocysteine showed no correlation with vitamin B₁₂ level.⁶

Further complicating things, some conditions can cause spuriously increased vitamin B₁₂ levels and thus might cause the appearance of normal vitamin B₁₂ levels when the patient is actually deficient.⁷ Examples include occult malignancy, myeloproliferative neoplasms, alcoholic liver disease, kidney disease, and nitrous oxide exposure (the latter of which is unique in that it can also cause true vitamin B₁₂ deficiency, as evidenced by clinical symptoms and high MMA levels).^8,9

Lastly, autoantibodies to intrinsic factor in individuals with pernicious anemia may compete with intrinsic factor in the chemiluminescence assay and result in spuriously normal vitamin B₁₂ levels in the presence of true deficiency.^10-12 If the vitamin B₁₂ level is very high (eg, 800 pg/mL), we do not worry about this effect in the absence of clinical features suggesting vitamin B₁₂ deficiency; however, if the vitamin B₁₂ level is borderline or low-normal and/or other clinical features suggest vitamin B₁₂ deficiency, it is prudent to obtain other testing such as an MMA level.

Dr. Ulin:

We are also joined by Dr. Rahul Ganatra, who cared for the patient at the time the diagnosis was made. Dr. Ganatra, can you share the final diagnosis and provide an update on the patient?

Rahul Ganatra, MD, MPH, Director of Continuing Medical Education, VABHS:

The patient’s hemoglobin rose to 6.9 g/dL after transfusion of 2 units of packed red blood cells, and his dyspnea on exertion and fatigue improved. Iron studies, serum thiamine, serum folate, ADAMTS13 activity levels, and AM cortisol level were normal. Upon closer examination of the peripheral blood smear, rare hypersegmented neutrophils were noted. Serum B₁₂ level returned below assay (< 146 pg/mL), and serum MMA was 50,800 nmol/L, confirming the diagnosis of severe vitamin B₁₂ deficiency. Antibodies against intrinsic factor were detected, confirming the diagnosis of pernicious anemia. Treatment was initiated with intramuscular cyanocobalamin every other day and was transitioned to weekly dosing at the time of hospital discharge. After excluding adrenal insufficiency, his levothyroxine dose was increased. Finally, a liver mass biopsy confirmed a concomitant diagnosis of HCC. The patient was discharged home. Five weeks after discharge, his serum B₁₂ level rose to > 1000 pg/mL, and 10 months after discharge, his TSH fell to 0.97 uIU/mL. Several months later, he underwent stereotactic body radiotherapy for the HCC. One year after his initial presentation, he has not resumed work as a barber.

Case Presentation: A 65-year-old male veteran presented to the Veterans Affairs Boston Healthcare System (VABHS) emergency department with progressive fatigue, dyspnea on exertion, lightheadedness, and falls over the last month. New bilateral lower extremity numbness up to his knees developed in the week prior to admission and prompted him to seek care. Additional history included 2 episodes of transient loss of consciousness resulting in falls and a week of diarrhea, which had resolved. His medical history was notable for hypothyroidism secondary to Hashimoto thyroiditis, seizure disorder, vitiligo, treated hepatitis C virus (HCV) infection, alcohol use disorder in remission, diabetes mellitus, posttraumatic stress disorder, and traumatic brain injury. His medications included levothyroxine and carbamazepine. He previously worked as a barber but recently had stopped due to cognitive impairment. On initial evaluation, the patient's vital signs included a temperature of 36.3 °C, heart rate of 77 beats per minute, blood pressure of 139/83 mm Hg, respiratory rate of 18 breaths per minute, and 99% oxygen saturation while breathing ambient air. Physical examination was notable for a frail-appearing man in no acute distress. His conjunctivae were pale, and cardiac auscultation revealed a normal heart rate and irregularly irregular heart rhythm. A neurologic examination revealed decreased vibratory sensation in both feet, delayed and minimal speech, and a blunted affect. His skin was warm and dry with patchy hypopigmentation across the face and forehead. Laboratory results are shown in the Table. Testing 2 years previously found the patient's hemoglobin to be 11.4 g/dL and serum creatinine to be 1.7 mg/dL. A peripheral blood smear showed anisocytosis, hypochromia, decreased platelets, ovalocytes, elliptocytes, and rare teardrop cells, with no schistocytes present. Chest radiography and computed tomography of the head were unremarkable. An abdominal ultrasound revealed a complex hypoechoic mass with peripheral rim vascularity in the right hepatic lobe measuring 3.9 cm × 3.6 cm × 3.9 cm.

Lindsey Ulin, MD, Chief Medical Resident, VABHS and Brigham and Women’s Hospital (BWH):

To build the initial differential diagnosis, we are joined today by 3 internal medicine residents who were not involved in the care of this patient. Dr. Hickey, Dr. Ross and Dr. Manivannan, how did you approach this case?

Meghan Hickey, MD, Senior Internal Medicine Resident, VABHS and Boston Medical Center (BMC):

The constellation of fatigue, weakness, blunted affect, and delayed, minimal speech suggested central nervous system involvement, which I sought to unify with hemolytic anemia and his liver mass. The first diagnosis I considered was Wilson disease; however, this genetic disorder of copper metabolism often presents with liver failure or cirrhosis in young or middle-aged women, so this presentation would be atypical. Next, given the hypopigmentation was reported only on sun-exposed areas of the patient’s face, I considered possibilities other than vitiligo to avoid diagnostic anchoring. One such alternate diagnosis is porphyria cutanea tarda (PCT), which presents in middle-aged and older adults with a photosensitive dermatitis that can include acute sensory deficits. Manifestations of PCT can be triggered by alcohol consumption, though his alcohol use disorder was thought to be in remission, as well as HCV, for which he previously received treatment. However, anemia is uncommon in PCT, so the patient’s low hemoglobin would not be explained by this diagnosis. Lastly, I considered thrombotic thrombocytopenic purpura (TTP) given his anemia, thrombocytopenia, and neurologic symptoms; however, the patient did not have fever or a clear inciting cause, his renal dysfunction was relatively mild, and the peripheral blood smear revealed no schistocytes, which should be present in TTP.

Caroline Ross, MD, and Alan Manivannan, MD; Senior Internal Medicine Residents, VABHS and BMC:

We noted several salient features in the history and physical examination. First, we sought to explain the bilateral lower extremity numbness and decreased vibratory sensation in the feet leading to falls. We also considered his anemia and thrombocytopenia with signs of hemolysis including elevated lactate dehydrogenase (LDH), low haptoglobin, and elevated total bilirubin; however, with normal coagulation parameters. These results initially raised our concern for a thrombotic microangiopathy (TMA) such as TTP. However, the peripheral smear lacked schistocytes, making this less likely. The combination of his neurologic symptoms and TMA-like laboratory findings but without schistocytes raised our concern for vitamin B12 deficiency. Vitamin B12 deficiency can cause a pseudo-TMA picture with laboratory finding similar to TTP; however, schistocytes are typically absent. We also considered the possibility of hepatocellular carcinoma (HCC) with bone marrow infiltration leading to anemia given the finding of a liver mass on his abdominal ultrasound and low reticulocyte index. However, this would not explain his hemolysis. We also considered chronic disseminated intravascular coagulation in the setting of a malignancy as a contributor, but again, the smear lacked schistocytes and his coagulation parameters were normal. Finally, we considered a primary bone marrow process such as myelodysplastic syndrome due to the bicytopenia with poor bone marrow response and smear with tear drop cells and elliptocytes. However, we felt this was less likely as this would not explain his hemolytic anemia.

Dr. Ulin:

To refine the differential diagnosis, we are joined by an expert clinician who was also not involved in the care of this patient to describe his approach to this case. Dr. Orlander, can you walk us through your clinical reasoning?

Jay Orlander, MD, MPH: Professor of Medicine, Section of General Internal Medicine, Boston University Chobanian & Avedisian School of Medicine, Associate Chief, Medical Service, VABHS:

I will first comment on the hepatic mass. The hypoechoic liver mass with peripheral vascularity suggests a growing tumor. The patient has a history of substance use disorder with alcohol and treated HCV. He remains at increased risk for HCC even after prior successful HCV treatment and has 2 of 4 known risk factors for developing HCC— diabetes mellitus and alcohol use—the other 2 being underlying metabolic dysfunctionassociated steatotic liver disease (MASLD) and the presence of hepatic fibrosis, which we have not yet assessed. Worsening liver function can lead to cognitive issues and alcohol to peripheral neuropathy, but his story is not consistent with this. For his liver mass, I recommend a nonurgent magnetic resonance image for further evaluation.

Next, let’s consider his markedly elevated thyrotropin (TSH). Cognitive impairment along with lethargy, fatigue, and decreased exercise tolerance can be prominent features in severe hypothyroidism, but this diagnosis would not explain his hematologic findings.¹

I view the principal finding of his laboratory testing as being that his bone marrow is failing to maintain adequate blood elements. He has a markedly low hematocrit along with low platelets and low-normal white blood cell counts. There is an absence of schistocytes on the blood smear, and after correcting his reticulocyte count for his degree of anemia (observed reticulocyte percentage [0.8%] x observed hematocrit [15.3%] / expected hematocrit [40%]), results in a reticulocyte index of 0.12, which is low. This suggests his bone marrow is failing to manufacture red blood cells at an appropriate rate. His haptoglobin is unmeasurable, so there is some free heme circulating. Hence, I infer that hemolysis and ineffective erythropoiesis are both occurring within the bone marrow, which also explains the slight elevation in bilirubin.

Intramedullary hemolysis with a markedly elevated LDH can be seen in severe vitamin B₁₂ deficiency, which has many causes, but one cause in particular warrants consideration in this case: pernicious anemia. Pernicious anemia has an overall prevalence of about 0.1%, but is more common in older adults, and is estimated to be present in 2% to 3% of adults aged > 65 years.² Prevalence is also increased in patients with other autoimmune diseases such as vitiligo and hypothyroidism, which our patient has.³ The pathophysiology of pernicious anemia relates to either autoimmune gastric parietal cell destruction and/or the development of antibodies against intrinsic factor, which is required for absorption of vitamin B₁₂. Early disease may present with macrocytosis and a normal hemoglobin initially, but anemia develops over time if left untreated. When the primary cause of pernicious anemia is gastric parietal cell destruction, there is also an associated lack of stomach acid production (achlorhydria) with resulting poor micronutrient absorption; specifically, vitamin D, vitamin C, and iron. Hence, 30% of patients diagnosed with pernicious anemia have concurrent iron deficiency, which may counteract macrocytosis and result in a normal mean corpuscular volume. 4 Some medications are also poorly absorbed in achlorhydric states, such as levothyroxine, and treatment doses need to be increased, which could explain his markedly elevated TSH despite presumed medication adherence.

Vitamin B₁₂ is essential for both the peripheral and central nervous systems. Longstanding severe B₁₂ deficiency can explain all of his neurological and neurocognitive changes. The most common neurologic findings in B₁₂ deficiency are symmetric paresthesias or numbness and gait problems. The sensory neuropathy affects the lower extremities more commonly than the upper. Untreated, patients can develop progressive weakness, ataxia, and orthostatic hypotension with syncope, as well as neuropsychiatric changes including depression or mood impairment, cognitive slowing, forgetfulness, and dementia.

Dr. Ulin:

Dr. Orlander, which pieces of objective data are most important in forming your differential diagnosis, and what tests would you obtain next?

Dr. Orlander:

The 3 most salient laboratory tests to me are a complete blood count, with all cell lines impacted but the hemoglobin and hematocrit most dramatically impacted, reticulocyte count of 0.8%, which is inappropriately low and hence suggests a hypoproliferative anemia, and the elevated LDH > 5000 IU/L.

Since my suspected diagnosis is pernicious anemia, I would obtain a blood smear looking for hypersegmented neutrophils, > 1 white blood cells with 5 lobes, or 1 with 6 lobes, which should clinch the diagnosis. Methylmalonic acid (MMA) levels are the most sensitive test for B₁₂ deficiency, so I would also obtain that. Finally, I would check a B₁₂ level, since in a patient with pernicious anemia, I would expect the level to be < 200 pg/mL.

Dr. Ulin:

Before we reveal the results of the patient’s additional workup, how do you approach interpreting B₁₂ levels?

Dr. Orlander:

Measuring B12 can sometimes be problematic: the normal range is considered 200 to 900 pg/mL, but patients with measured low-normal levels in the range of 200 to 400 pg/mL can actually be physiologically deficient. There are also several common causes of falsely low and falsely high B₁₂ levels in the absence of B₁₂ deficiency. Hence, for patients with mild symptoms that could be due to B₁₂ deficiency, many clinicians choose to just treat with B₁₂ supplementation, deeming it safer to treat than miss an early diagnosis. B₁₂ is involved in hydrogen transfer to convert MMA into succinyl-CoA and hence true vitamin B₁₂ deficiency causes an increase in MMA.

Decreased production of vitamin B12 binding proteins, like haptocorrin, has been proposed as the mechanism for spurious low values.⁵ Certain conditions or medications can also cause spurious low serum vitamin B₁₂ levels and thus might cause the appearance of vitamin B₁₂ deficiency when the patient is not deficient. Examples include multiple myeloma, HIV infection, pregnancy, oral contraceptives, and phenytoin use. An example of spuriously low vitamin B₁₂ level in pregnancy was demonstrated in a series of 50 pregnant individuals with low vitamin B₁₂ levels (45-199 pg/mL), in whom metabolite testing for MMA and homocysteine showed no correlation with vitamin B₁₂ level.⁶

Further complicating things, some conditions can cause spuriously increased vitamin B₁₂ levels and thus might cause the appearance of normal vitamin B₁₂ levels when the patient is actually deficient.⁷ Examples include occult malignancy, myeloproliferative neoplasms, alcoholic liver disease, kidney disease, and nitrous oxide exposure (the latter of which is unique in that it can also cause true vitamin B₁₂ deficiency, as evidenced by clinical symptoms and high MMA levels).^8,9

Lastly, autoantibodies to intrinsic factor in individuals with pernicious anemia may compete with intrinsic factor in the chemiluminescence assay and result in spuriously normal vitamin B₁₂ levels in the presence of true deficiency.^10-12 If the vitamin B₁₂ level is very high (eg, 800 pg/mL), we do not worry about this effect in the absence of clinical features suggesting vitamin B₁₂ deficiency; however, if the vitamin B₁₂ level is borderline or low-normal and/or other clinical features suggest vitamin B₁₂ deficiency, it is prudent to obtain other testing such as an MMA level.

Dr. Ulin:

We are also joined by Dr. Rahul Ganatra, who cared for the patient at the time the diagnosis was made. Dr. Ganatra, can you share the final diagnosis and provide an update on the patient?

Rahul Ganatra, MD, MPH, Director of Continuing Medical Education, VABHS:

The patient’s hemoglobin rose to 6.9 g/dL after transfusion of 2 units of packed red blood cells, and his dyspnea on exertion and fatigue improved. Iron studies, serum thiamine, serum folate, ADAMTS13 activity levels, and AM cortisol level were normal. Upon closer examination of the peripheral blood smear, rare hypersegmented neutrophils were noted. Serum B₁₂ level returned below assay (< 146 pg/mL), and serum MMA was 50,800 nmol/L, confirming the diagnosis of severe vitamin B₁₂ deficiency. Antibodies against intrinsic factor were detected, confirming the diagnosis of pernicious anemia. Treatment was initiated with intramuscular cyanocobalamin every other day and was transitioned to weekly dosing at the time of hospital discharge. After excluding adrenal insufficiency, his levothyroxine dose was increased. Finally, a liver mass biopsy confirmed a concomitant diagnosis of HCC. The patient was discharged home. Five weeks after discharge, his serum B₁₂ level rose to > 1000 pg/mL, and 10 months after discharge, his TSH fell to 0.97 uIU/mL. Several months later, he underwent stereotactic body radiotherapy for the HCC. One year after his initial presentation, he has not resumed work as a barber.

Case Presentation: A 65-year-old male veteran presented to the Veterans Affairs Boston Healthcare System (VABHS) emergency department with progressive fatigue, dyspnea on exertion, lightheadedness, and falls over the last month. New bilateral lower extremity numbness up to his knees developed in the week prior to admission and prompted him to seek care. Additional history included 2 episodes of transient loss of consciousness resulting in falls and a week of diarrhea, which had resolved. His medical history was notable for hypothyroidism secondary to Hashimoto thyroiditis, seizure disorder, vitiligo, treated hepatitis C virus (HCV) infection, alcohol use disorder in remission, diabetes mellitus, posttraumatic stress disorder, and traumatic brain injury. His medications included levothyroxine and carbamazepine. He previously worked as a barber but recently had stopped due to cognitive impairment. On initial evaluation, the patient's vital signs included a temperature of 36.3 °C, heart rate of 77 beats per minute, blood pressure of 139/83 mm Hg, respiratory rate of 18 breaths per minute, and 99% oxygen saturation while breathing ambient air. Physical examination was notable for a frail-appearing man in no acute distress. His conjunctivae were pale, and cardiac auscultation revealed a normal heart rate and irregularly irregular heart rhythm. A neurologic examination revealed decreased vibratory sensation in both feet, delayed and minimal speech, and a blunted affect. His skin was warm and dry with patchy hypopigmentation across the face and forehead. Laboratory results are shown in the Table. Testing 2 years previously found the patient's hemoglobin to be 11.4 g/dL and serum creatinine to be 1.7 mg/dL. A peripheral blood smear showed anisocytosis, hypochromia, decreased platelets, ovalocytes, elliptocytes, and rare teardrop cells, with no schistocytes present. Chest radiography and computed tomography of the head were unremarkable. An abdominal ultrasound revealed a complex hypoechoic mass with peripheral rim vascularity in the right hepatic lobe measuring 3.9 cm × 3.6 cm × 3.9 cm.

Lindsey Ulin, MD, Chief Medical Resident, VABHS and Brigham and Women’s Hospital (BWH):

To build the initial differential diagnosis, we are joined today by 3 internal medicine residents who were not involved in the care of this patient. Dr. Hickey, Dr. Ross and Dr. Manivannan, how did you approach this case?

Meghan Hickey, MD, Senior Internal Medicine Resident, VABHS and Boston Medical Center (BMC):

The constellation of fatigue, weakness, blunted affect, and delayed, minimal speech suggested central nervous system involvement, which I sought to unify with hemolytic anemia and his liver mass. The first diagnosis I considered was Wilson disease; however, this genetic disorder of copper metabolism often presents with liver failure or cirrhosis in young or middle-aged women, so this presentation would be atypical. Next, given the hypopigmentation was reported only on sun-exposed areas of the patient’s face, I considered possibilities other than vitiligo to avoid diagnostic anchoring. One such alternate diagnosis is porphyria cutanea tarda (PCT), which presents in middle-aged and older adults with a photosensitive dermatitis that can include acute sensory deficits. Manifestations of PCT can be triggered by alcohol consumption, though his alcohol use disorder was thought to be in remission, as well as HCV, for which he previously received treatment. However, anemia is uncommon in PCT, so the patient’s low hemoglobin would not be explained by this diagnosis. Lastly, I considered thrombotic thrombocytopenic purpura (TTP) given his anemia, thrombocytopenia, and neurologic symptoms; however, the patient did not have fever or a clear inciting cause, his renal dysfunction was relatively mild, and the peripheral blood smear revealed no schistocytes, which should be present in TTP.

Caroline Ross, MD, and Alan Manivannan, MD; Senior Internal Medicine Residents, VABHS and BMC:

We noted several salient features in the history and physical examination. First, we sought to explain the bilateral lower extremity numbness and decreased vibratory sensation in the feet leading to falls. We also considered his anemia and thrombocytopenia with signs of hemolysis including elevated lactate dehydrogenase (LDH), low haptoglobin, and elevated total bilirubin; however, with normal coagulation parameters. These results initially raised our concern for a thrombotic microangiopathy (TMA) such as TTP. However, the peripheral smear lacked schistocytes, making this less likely. The combination of his neurologic symptoms and TMA-like laboratory findings but without schistocytes raised our concern for vitamin B12 deficiency. Vitamin B12 deficiency can cause a pseudo-TMA picture with laboratory finding similar to TTP; however, schistocytes are typically absent. We also considered the possibility of hepatocellular carcinoma (HCC) with bone marrow infiltration leading to anemia given the finding of a liver mass on his abdominal ultrasound and low reticulocyte index. However, this would not explain his hemolysis. We also considered chronic disseminated intravascular coagulation in the setting of a malignancy as a contributor, but again, the smear lacked schistocytes and his coagulation parameters were normal. Finally, we considered a primary bone marrow process such as myelodysplastic syndrome due to the bicytopenia with poor bone marrow response and smear with tear drop cells and elliptocytes. However, we felt this was less likely as this would not explain his hemolytic anemia.

Dr. Ulin:

To refine the differential diagnosis, we are joined by an expert clinician who was also not involved in the care of this patient to describe his approach to this case. Dr. Orlander, can you walk us through your clinical reasoning?

Jay Orlander, MD, MPH: Professor of Medicine, Section of General Internal Medicine, Boston University Chobanian & Avedisian School of Medicine, Associate Chief, Medical Service, VABHS:

I will first comment on the hepatic mass. The hypoechoic liver mass with peripheral vascularity suggests a growing tumor. The patient has a history of substance use disorder with alcohol and treated HCV. He remains at increased risk for HCC even after prior successful HCV treatment and has 2 of 4 known risk factors for developing HCC— diabetes mellitus and alcohol use—the other 2 being underlying metabolic dysfunctionassociated steatotic liver disease (MASLD) and the presence of hepatic fibrosis, which we have not yet assessed. Worsening liver function can lead to cognitive issues and alcohol to peripheral neuropathy, but his story is not consistent with this. For his liver mass, I recommend a nonurgent magnetic resonance image for further evaluation.

Next, let’s consider his markedly elevated thyrotropin (TSH). Cognitive impairment along with lethargy, fatigue, and decreased exercise tolerance can be prominent features in severe hypothyroidism, but this diagnosis would not explain his hematologic findings.¹

I view the principal finding of his laboratory testing as being that his bone marrow is failing to maintain adequate blood elements. He has a markedly low hematocrit along with low platelets and low-normal white blood cell counts. There is an absence of schistocytes on the blood smear, and after correcting his reticulocyte count for his degree of anemia (observed reticulocyte percentage [0.8%] x observed hematocrit [15.3%] / expected hematocrit [40%]), results in a reticulocyte index of 0.12, which is low. This suggests his bone marrow is failing to manufacture red blood cells at an appropriate rate. His haptoglobin is unmeasurable, so there is some free heme circulating. Hence, I infer that hemolysis and ineffective erythropoiesis are both occurring within the bone marrow, which also explains the slight elevation in bilirubin.

Intramedullary hemolysis with a markedly elevated LDH can be seen in severe vitamin B₁₂ deficiency, which has many causes, but one cause in particular warrants consideration in this case: pernicious anemia. Pernicious anemia has an overall prevalence of about 0.1%, but is more common in older adults, and is estimated to be present in 2% to 3% of adults aged > 65 years.² Prevalence is also increased in patients with other autoimmune diseases such as vitiligo and hypothyroidism, which our patient has.³ The pathophysiology of pernicious anemia relates to either autoimmune gastric parietal cell destruction and/or the development of antibodies against intrinsic factor, which is required for absorption of vitamin B₁₂. Early disease may present with macrocytosis and a normal hemoglobin initially, but anemia develops over time if left untreated. When the primary cause of pernicious anemia is gastric parietal cell destruction, there is also an associated lack of stomach acid production (achlorhydria) with resulting poor micronutrient absorption; specifically, vitamin D, vitamin C, and iron. Hence, 30% of patients diagnosed with pernicious anemia have concurrent iron deficiency, which may counteract macrocytosis and result in a normal mean corpuscular volume. 4 Some medications are also poorly absorbed in achlorhydric states, such as levothyroxine, and treatment doses need to be increased, which could explain his markedly elevated TSH despite presumed medication adherence.

Vitamin B₁₂ is essential for both the peripheral and central nervous systems. Longstanding severe B₁₂ deficiency can explain all of his neurological and neurocognitive changes. The most common neurologic findings in B₁₂ deficiency are symmetric paresthesias or numbness and gait problems. The sensory neuropathy affects the lower extremities more commonly than the upper. Untreated, patients can develop progressive weakness, ataxia, and orthostatic hypotension with syncope, as well as neuropsychiatric changes including depression or mood impairment, cognitive slowing, forgetfulness, and dementia.

Dr. Ulin:

Dr. Orlander, which pieces of objective data are most important in forming your differential diagnosis, and what tests would you obtain next?

Dr. Orlander:

The 3 most salient laboratory tests to me are a complete blood count, with all cell lines impacted but the hemoglobin and hematocrit most dramatically impacted, reticulocyte count of 0.8%, which is inappropriately low and hence suggests a hypoproliferative anemia, and the elevated LDH > 5000 IU/L.

Since my suspected diagnosis is pernicious anemia, I would obtain a blood smear looking for hypersegmented neutrophils, > 1 white blood cells with 5 lobes, or 1 with 6 lobes, which should clinch the diagnosis. Methylmalonic acid (MMA) levels are the most sensitive test for B₁₂ deficiency, so I would also obtain that. Finally, I would check a B₁₂ level, since in a patient with pernicious anemia, I would expect the level to be < 200 pg/mL.

Dr. Ulin:

Before we reveal the results of the patient’s additional workup, how do you approach interpreting B₁₂ levels?

Dr. Orlander:

Measuring B12 can sometimes be problematic: the normal range is considered 200 to 900 pg/mL, but patients with measured low-normal levels in the range of 200 to 400 pg/mL can actually be physiologically deficient. There are also several common causes of falsely low and falsely high B₁₂ levels in the absence of B₁₂ deficiency. Hence, for patients with mild symptoms that could be due to B₁₂ deficiency, many clinicians choose to just treat with B₁₂ supplementation, deeming it safer to treat than miss an early diagnosis. B₁₂ is involved in hydrogen transfer to convert MMA into succinyl-CoA and hence true vitamin B₁₂ deficiency causes an increase in MMA.

Decreased production of vitamin B12 binding proteins, like haptocorrin, has been proposed as the mechanism for spurious low values.⁵ Certain conditions or medications can also cause spurious low serum vitamin B₁₂ levels and thus might cause the appearance of vitamin B₁₂ deficiency when the patient is not deficient. Examples include multiple myeloma, HIV infection, pregnancy, oral contraceptives, and phenytoin use. An example of spuriously low vitamin B₁₂ level in pregnancy was demonstrated in a series of 50 pregnant individuals with low vitamin B₁₂ levels (45-199 pg/mL), in whom metabolite testing for MMA and homocysteine showed no correlation with vitamin B₁₂ level.⁶

Further complicating things, some conditions can cause spuriously increased vitamin B₁₂ levels and thus might cause the appearance of normal vitamin B₁₂ levels when the patient is actually deficient.⁷ Examples include occult malignancy, myeloproliferative neoplasms, alcoholic liver disease, kidney disease, and nitrous oxide exposure (the latter of which is unique in that it can also cause true vitamin B₁₂ deficiency, as evidenced by clinical symptoms and high MMA levels).^8,9

Lastly, autoantibodies to intrinsic factor in individuals with pernicious anemia may compete with intrinsic factor in the chemiluminescence assay and result in spuriously normal vitamin B₁₂ levels in the presence of true deficiency.^10-12 If the vitamin B₁₂ level is very high (eg, 800 pg/mL), we do not worry about this effect in the absence of clinical features suggesting vitamin B₁₂ deficiency; however, if the vitamin B₁₂ level is borderline or low-normal and/or other clinical features suggest vitamin B₁₂ deficiency, it is prudent to obtain other testing such as an MMA level.

Dr. Ulin:

We are also joined by Dr. Rahul Ganatra, who cared for the patient at the time the diagnosis was made. Dr. Ganatra, can you share the final diagnosis and provide an update on the patient?

Rahul Ganatra, MD, MPH, Director of Continuing Medical Education, VABHS:

The patient’s hemoglobin rose to 6.9 g/dL after transfusion of 2 units of packed red blood cells, and his dyspnea on exertion and fatigue improved. Iron studies, serum thiamine, serum folate, ADAMTS13 activity levels, and AM cortisol level were normal. Upon closer examination of the peripheral blood smear, rare hypersegmented neutrophils were noted. Serum B₁₂ level returned below assay (< 146 pg/mL), and serum MMA was 50,800 nmol/L, confirming the diagnosis of severe vitamin B₁₂ deficiency. Antibodies against intrinsic factor were detected, confirming the diagnosis of pernicious anemia. Treatment was initiated with intramuscular cyanocobalamin every other day and was transitioned to weekly dosing at the time of hospital discharge. After excluding adrenal insufficiency, his levothyroxine dose was increased. Finally, a liver mass biopsy confirmed a concomitant diagnosis of HCC. The patient was discharged home. Five weeks after discharge, his serum B₁₂ level rose to > 1000 pg/mL, and 10 months after discharge, his TSH fell to 0.97 uIU/mL. Several months later, he underwent stereotactic body radiotherapy for the HCC. One year after his initial presentation, he has not resumed work as a barber.

The United States’ initial public health response to the COVID-19 pandemic included containment measures that varied by state but generally required closing or suspending schools, nonessential businesses, and travel (commonly called lockdown).¹ During these periods, hospitalizations for serious and common conditions declined.^2,3 In Massachusetts, a state of emergency was declared on March 10, 2020, which remained in place until May 18, 2020, when a phased reopening of businesses began.

Although the evidence on the mental health impact of containment periods has been mixed, it has been suggested that these measures could lead to increases in alcohol-related hospitalizations.⁴ Social isolation and increased psychosocial and financial stressors raise the risk of relapse among patients with substance use disorders.^5-7 Marketing and survey data from the US and United Kingdom from the early months of the pandemic suggest that in-home alcohol consumption and sales of alcoholic beverages increased, while consumption of alcohol outside the home decreased.^8-10 Other research has shown an increase in the percentage—but not necessarily the absolute number—of emergency department (ED) visits and hospitalizations for alcohol-related diagnoses during periods of containment.^11,12 At least 1 study suggests that alcohol-related deaths increased beginning in the lockdown period and persisting into mid-2021.¹³

Because earlier studies suggest that lockdown periods are associated with increased alcohol consumption and relapse of alcohol use disorder, we hypothesized that the spring 2020 lockdown period in Massachusetts would be associated temporally with an increase in alcohol-related hospitalizations. To evaluate this hypothesis, we examined all hospitalizations in the US Department of Veterans Affairs (VA) Boston Healthcare System (VABHS) before, during, and after this lockdown period. VABHS includes a 160-bed acute care hospital and a 50-bed inpatient psychiatric facility.

Methods

We conducted an interrupted time-series analysis including all inpatient hospitalizations at VABHS from January 1, 2017, to December 31, 2020, to compare the daily number of alcohol-related hospitalizations across 3 exposure groups: prelockdown (the reference group, 1/1/2017-3/9/2020); lockdown (3/10/2020-5/18/2020); and postlockdown (5/19/2020-12/31/2020).

The VA Corporate Data Warehouse at VABHS was queried to identify all hospitalizations on the medical, psychiatry, and neurology services during the study period. Hospitalizations were considered alcohol-related if the International Statistical Classification of Diseases, Tenth Revision (ICD-10) primary diagnosis code (the main reason for hospitalization) was defined as an alcohol-related diagnosis by the VA Centralized Interactive Phenomics Resource (eAppendix 1, available online at doi:10.1278/fp.0404). This database, which has been previously used for COVID-19 research, is a catalog and knowledge-sharing platform of VA electronic health record–based phenotype algorithms, definitions, and metadata that builds on the Million Veteran Program and Cooperative Studies Program.^14,15 Hospitalizations under observation status were excluded.

To examine whether alcohol-related hospitalizations could have been categorized as COVID-19 when the conditions were co-occurring, we identified 244 hospitalizations coded with a primary ICD-10 code for COVID-19 during the lockdown and postlockdown periods. At the time of admission, each hospitalization carries an initial (free text) diagnosis, of which 3 had an initial diagnosis related to alcohol use. The population at risk for alcohol-related hospitalizations was estimated as the number of patients actively engaged in care at the VABHS. This was defined as the number of patients enrolled in VA care who have previously received any VA care; patients who are enrolled but have never received VA care were excluded from the population-at-risk denominator. Population-at-risk data were available for each fiscal year (FY) of the study period (9/30-10/1); the following population-at-risk sizes were used: 38,057 for FY 2017, 38,527 for FY 2018, 39,472 for FY 2019, and 37,893 for FY 2020.

The primary outcome was the daily number of alcohol-related hospitalizations in the prelockdown, lockdown, and postlockdown periods. A sensitivity analysis was performed using an alternate definition of the primary outcome using a broader set of alcohol-related ICD-10 codes (eAppendix 2, available online at doi:10.1278/fp.0404).

Statistical Analysis

To visually examine hospitalization trends during the study period, we generated a smoothed time-series plot of the 7-day moving average of the daily number of all-cause hospitalizations and the daily number of alcohol-related hospitalizations from January 1, 2017, to December 31, 2020. We used multivariable regression to model the daily number of alcohol-related hospitalizations over prelockdown (the reference group), lockdown, and postlockdown. In addition to the exposure, we included the following covariates in our model: day of the week, calendar date (to account for secular trends), and harmonic polynomials of the day of the year (to account for seasonal variation).¹⁶

We also examined models that included the daily total number of hospitalizations to account for the reduced likelihood of hospital admission for any reason during the pandemic. We used generalized linear models with a Poisson link to generate rate ratios and corresponding 95% CIs for estimates of the daily number of alcohol-related hospitalizations. We estimated the population incidence of alcohol-related hospitalizations per 100,000 patient-months for the exposure periods using the population denominators previously described. All analyses were performed in Stata 16.1.

Results

During the study period, 27,508 hospitalizations were available for analysis. The 7-day moving average of total daily hospitalizations and total daily alcohol-related hospitalizations over time for the period January 1, 2017, to December 31, 2020, are shown in the Figure.

The incidence of alcohol-related hospitalizations in the population dropped from 72 per 100,000 patient-months to 10 per 100,000 patient-months during the lockdown period and increased to 46 per 100,000 patient-months during the postlockdown period (Table).

Discussion

During the spring 2020 COVID-19 lockdown period in Massachusetts, the daily number of VABHS alcohol-related hospitalizations decreased by nearly 80% compared with the prelockdown period. During the postlockdown period, the daily number of alcohol-related hospitalizations increased but only to 72% of the prelockdown baseline by the end of December 2020. A similar trend was observed for all-cause hospitalizations for the same exposure periods.

These results differ from 2 related studies on the effect of the COVID-19 pandemic on alcohol-related hospitalizations.^10,11 In a retrospective study of ED visits to 4 hospitals in New York City, Schimmel and colleagues reported that from March 1 to 31, 2020 (the initial COVID-19 peak), hospital visits for alcohol withdrawal increased while those for alcohol use decreased.¹⁰ However, these results are reported as a percentage of total ED visits rather than the total number of visits, which are vulnerable to spurious correlation because of concomitant changes in the total number of ED visits. In their study, the absolute number of alcohol-related ED visits did not increase during the initial 2020 COVID-19 peak, and the number of visits for alcohol withdrawal syndrome declined slightly (195 in 2019 and 180 in 2020). However, the percentage of visits increased from 7% to 10% because of a greater decline in total ED visits. This pattern of decline in the number of alcohol-related ED visits, accompanied by an increase in the percentage of alcohol-related ED visits, has been observed in at least 1 nationwide surveillance study.¹⁷ This apparent increase does not reflect an absolute increase in ED visits for alcohol withdrawal syndrome and represents a greater relative decline in visits for other causes during the study period.

Sharma and colleagues reported an increase in the percentage of patients who developed alcohol withdrawal syndrome while hospitalized in Delaware per 1000 hospitalizations during consecutive 2-week periods during the pandemic in 2020 compared with corresponding weeks in 2019.¹¹ The greatest increase occurred during the last 2 weeks of the Delaware stay-at-home order. The Clinical Institute Withdrawal Assessment of Alcohol Scale, revised (CIWA-Ar) score of > 8 was used to define alcohol withdrawal syndrome. The American Society of Addiction Medicine does not recommend using CIWA-Ar to diagnose alcohol withdrawal syndrome because the scale was developed to monitor response to treatment, not to establish a diagnosis.¹⁸

Although the true population incidence of alcohol-related hospitalizations is difficult to estimate because the size of the population at risk (ie, the denominator) often is not known, the total number of hospitalizations is not a reliable surrogate.¹⁹ Individuals hospitalized for nonalcohol causes are no longer at risk for alcohol-related hospitalization.

In our study, we assume the population at risk during the study period is constant and model changes in the absolute number—rather than percentage—of alcohol-related ED visits. These absolute estimates of alcohol-related hospitalizations better reflect the true burden on the health care system and avoid the confounding effect of declining total ED visits and hospitalizations that could lead to artificially increased percentages and spurious correlation.²⁰ The absolute percentage of alcohol-related hospitalizations also decreased during this period; therefore, our results are not sensitive to this approach.

Several factors could have contributed to the decrease in alcohol-related hospitalizations. Our findings suggest that patient likelihood to seek care and clinician threshold to admit patients for alcohol-related conditions are influenced by external factors, in this case, a public health lockdown. Although our data do not inform why hospitalizations did not return to prelockdown levels, our experience suggests that limited bed capacity and longer length of stay might have contributed. Other hypotheses include a shift to outpatient care, increased use of telehealth (a significant focus early in the pandemic), and avoiding care for less severe alcohol-related complications because of lingering concerns about exposure to COVID-19 in health care settings reported early in the pandemic. Massachusetts experienced a particularly deadly outbreak of COVID-19 in the Soldiers’ Home, a long-term care facility for veterans in Holyoke.²¹

Evidence suggests that in-home consumption of alcohol increased during lockdowns.^8-10 Our results show that during this period hospitalizations for alcohol-related conditions decreased at VABHS, a large urban VA medical system, while alcohol-related deaths increased nationally.¹³ Although this observation is not evidence of causality, these outcomes could be related.

In the 2 decades before the pandemic, alcohol-related deaths increased by about 2% per year.²² From 2019 to 2020, there was a 25% increase that continued through 2021.¹³ Death certificate data often are inaccurate, and it is difficult to determine whether COVID-19 had a substantial contributing role to these deaths, particularly during the initial period when testing was limited or unavailable. Nonetheless, deaths due to alcohol-associated liver disease, overdoses involving alcohol, and alcohol-related traffic fatalities increased by > 10%.^13,23 These trends, along with a decrease in hospitalization for alcohol-related conditions, suggest missed opportunities for intervention with patients experiencing alcohol use disorder.

Limitations

In this study, hospitalizations under observation status were excluded, which could underestimate the total number of hospitalizations related to alcohol. We reasoned that this effect was likely to be small and not substantially different by year. ICD-10 codes were used to identify alcohol-related hospitalizations as any hospitalization with an included ICD-10 code listed as the primary discharge diagnosis code. This also likely underestimated the total number of alcohol-related hospitalizations. An ICD-10 code for COVID-19 was not in widespread use during our study period, which prohibited controlling explicitly for the volume of admissions due to COVID-19. The prelockdown period only contains data from the preceding 3 years, which might not be long enough for secular trends to become apparent. We assumed the population at risk remained constant when in reality, the net movement of patients into and out of VA care during the pandemic likely was more complex but not readily quantifiable. Nonetheless, the large drop in absolute number of alcohol-related hospitalizations is not likely to be sensitive to this change. In the absence of an objective measure of care-seeking behavior, we used the total daily number of hospitalizations as a surrogate for patient propensity to seek care. The total daily number of hospitalizations also reflects changes in physician admitting behavior over time. This allowed explicit modeling of care-seeking behavior as a covariate but does not capture other important determinants such as hospital capacity.

Conclusions

In this interrupted time-series analysis, the daily number of alcohol-related hospitalizations during the initial COVID-19 pandemic–associated lockdown period at VABHS decreased by 80% and remained 28% lower in the postlockdown period compared with the prepandemic baseline. In the context of evidence suggesting that alcohol-related mortality increased during the COVID-19 pandemic, alternate strategies to reach vulnerable individuals are needed. Because of high rates of relapse, hospitalization is an important opportunity to engage patients experiencing alcohol use disorder in treatment through referral to substance use treatment programs and medication-assisted therapy. Considering the reduction in alcohol-related hospitalizations during lockdown, other strategies are needed to ensure comprehensive and longitudinal care for this vulnerable population.

The United States’ initial public health response to the COVID-19 pandemic included containment measures that varied by state but generally required closing or suspending schools, nonessential businesses, and travel (commonly called lockdown).¹ During these periods, hospitalizations for serious and common conditions declined.^2,3 In Massachusetts, a state of emergency was declared on March 10, 2020, which remained in place until May 18, 2020, when a phased reopening of businesses began.

Although the evidence on the mental health impact of containment periods has been mixed, it has been suggested that these measures could lead to increases in alcohol-related hospitalizations.⁴ Social isolation and increased psychosocial and financial stressors raise the risk of relapse among patients with substance use disorders.^5-7 Marketing and survey data from the US and United Kingdom from the early months of the pandemic suggest that in-home alcohol consumption and sales of alcoholic beverages increased, while consumption of alcohol outside the home decreased.^8-10 Other research has shown an increase in the percentage—but not necessarily the absolute number—of emergency department (ED) visits and hospitalizations for alcohol-related diagnoses during periods of containment.^11,12 At least 1 study suggests that alcohol-related deaths increased beginning in the lockdown period and persisting into mid-2021.¹³

Because earlier studies suggest that lockdown periods are associated with increased alcohol consumption and relapse of alcohol use disorder, we hypothesized that the spring 2020 lockdown period in Massachusetts would be associated temporally with an increase in alcohol-related hospitalizations. To evaluate this hypothesis, we examined all hospitalizations in the US Department of Veterans Affairs (VA) Boston Healthcare System (VABHS) before, during, and after this lockdown period. VABHS includes a 160-bed acute care hospital and a 50-bed inpatient psychiatric facility.

Methods

We conducted an interrupted time-series analysis including all inpatient hospitalizations at VABHS from January 1, 2017, to December 31, 2020, to compare the daily number of alcohol-related hospitalizations across 3 exposure groups: prelockdown (the reference group, 1/1/2017-3/9/2020); lockdown (3/10/2020-5/18/2020); and postlockdown (5/19/2020-12/31/2020).

The VA Corporate Data Warehouse at VABHS was queried to identify all hospitalizations on the medical, psychiatry, and neurology services during the study period. Hospitalizations were considered alcohol-related if the International Statistical Classification of Diseases, Tenth Revision (ICD-10) primary diagnosis code (the main reason for hospitalization) was defined as an alcohol-related diagnosis by the VA Centralized Interactive Phenomics Resource (eAppendix 1, available online at doi:10.1278/fp.0404). This database, which has been previously used for COVID-19 research, is a catalog and knowledge-sharing platform of VA electronic health record–based phenotype algorithms, definitions, and metadata that builds on the Million Veteran Program and Cooperative Studies Program.^14,15 Hospitalizations under observation status were excluded.

To examine whether alcohol-related hospitalizations could have been categorized as COVID-19 when the conditions were co-occurring, we identified 244 hospitalizations coded with a primary ICD-10 code for COVID-19 during the lockdown and postlockdown periods. At the time of admission, each hospitalization carries an initial (free text) diagnosis, of which 3 had an initial diagnosis related to alcohol use. The population at risk for alcohol-related hospitalizations was estimated as the number of patients actively engaged in care at the VABHS. This was defined as the number of patients enrolled in VA care who have previously received any VA care; patients who are enrolled but have never received VA care were excluded from the population-at-risk denominator. Population-at-risk data were available for each fiscal year (FY) of the study period (9/30-10/1); the following population-at-risk sizes were used: 38,057 for FY 2017, 38,527 for FY 2018, 39,472 for FY 2019, and 37,893 for FY 2020.

The primary outcome was the daily number of alcohol-related hospitalizations in the prelockdown, lockdown, and postlockdown periods. A sensitivity analysis was performed using an alternate definition of the primary outcome using a broader set of alcohol-related ICD-10 codes (eAppendix 2, available online at doi:10.1278/fp.0404).

Statistical Analysis

To visually examine hospitalization trends during the study period, we generated a smoothed time-series plot of the 7-day moving average of the daily number of all-cause hospitalizations and the daily number of alcohol-related hospitalizations from January 1, 2017, to December 31, 2020. We used multivariable regression to model the daily number of alcohol-related hospitalizations over prelockdown (the reference group), lockdown, and postlockdown. In addition to the exposure, we included the following covariates in our model: day of the week, calendar date (to account for secular trends), and harmonic polynomials of the day of the year (to account for seasonal variation).¹⁶

We also examined models that included the daily total number of hospitalizations to account for the reduced likelihood of hospital admission for any reason during the pandemic. We used generalized linear models with a Poisson link to generate rate ratios and corresponding 95% CIs for estimates of the daily number of alcohol-related hospitalizations. We estimated the population incidence of alcohol-related hospitalizations per 100,000 patient-months for the exposure periods using the population denominators previously described. All analyses were performed in Stata 16.1.

Results

During the study period, 27,508 hospitalizations were available for analysis. The 7-day moving average of total daily hospitalizations and total daily alcohol-related hospitalizations over time for the period January 1, 2017, to December 31, 2020, are shown in the Figure.

The incidence of alcohol-related hospitalizations in the population dropped from 72 per 100,000 patient-months to 10 per 100,000 patient-months during the lockdown period and increased to 46 per 100,000 patient-months during the postlockdown period (Table).

Discussion

During the spring 2020 COVID-19 lockdown period in Massachusetts, the daily number of VABHS alcohol-related hospitalizations decreased by nearly 80% compared with the prelockdown period. During the postlockdown period, the daily number of alcohol-related hospitalizations increased but only to 72% of the prelockdown baseline by the end of December 2020. A similar trend was observed for all-cause hospitalizations for the same exposure periods.

These results differ from 2 related studies on the effect of the COVID-19 pandemic on alcohol-related hospitalizations.^10,11 In a retrospective study of ED visits to 4 hospitals in New York City, Schimmel and colleagues reported that from March 1 to 31, 2020 (the initial COVID-19 peak), hospital visits for alcohol withdrawal increased while those for alcohol use decreased.¹⁰ However, these results are reported as a percentage of total ED visits rather than the total number of visits, which are vulnerable to spurious correlation because of concomitant changes in the total number of ED visits. In their study, the absolute number of alcohol-related ED visits did not increase during the initial 2020 COVID-19 peak, and the number of visits for alcohol withdrawal syndrome declined slightly (195 in 2019 and 180 in 2020). However, the percentage of visits increased from 7% to 10% because of a greater decline in total ED visits. This pattern of decline in the number of alcohol-related ED visits, accompanied by an increase in the percentage of alcohol-related ED visits, has been observed in at least 1 nationwide surveillance study.¹⁷ This apparent increase does not reflect an absolute increase in ED visits for alcohol withdrawal syndrome and represents a greater relative decline in visits for other causes during the study period.

Sharma and colleagues reported an increase in the percentage of patients who developed alcohol withdrawal syndrome while hospitalized in Delaware per 1000 hospitalizations during consecutive 2-week periods during the pandemic in 2020 compared with corresponding weeks in 2019.¹¹ The greatest increase occurred during the last 2 weeks of the Delaware stay-at-home order. The Clinical Institute Withdrawal Assessment of Alcohol Scale, revised (CIWA-Ar) score of > 8 was used to define alcohol withdrawal syndrome. The American Society of Addiction Medicine does not recommend using CIWA-Ar to diagnose alcohol withdrawal syndrome because the scale was developed to monitor response to treatment, not to establish a diagnosis.¹⁸

Although the true population incidence of alcohol-related hospitalizations is difficult to estimate because the size of the population at risk (ie, the denominator) often is not known, the total number of hospitalizations is not a reliable surrogate.¹⁹ Individuals hospitalized for nonalcohol causes are no longer at risk for alcohol-related hospitalization.

In our study, we assume the population at risk during the study period is constant and model changes in the absolute number—rather than percentage—of alcohol-related ED visits. These absolute estimates of alcohol-related hospitalizations better reflect the true burden on the health care system and avoid the confounding effect of declining total ED visits and hospitalizations that could lead to artificially increased percentages and spurious correlation.²⁰ The absolute percentage of alcohol-related hospitalizations also decreased during this period; therefore, our results are not sensitive to this approach.

Several factors could have contributed to the decrease in alcohol-related hospitalizations. Our findings suggest that patient likelihood to seek care and clinician threshold to admit patients for alcohol-related conditions are influenced by external factors, in this case, a public health lockdown. Although our data do not inform why hospitalizations did not return to prelockdown levels, our experience suggests that limited bed capacity and longer length of stay might have contributed. Other hypotheses include a shift to outpatient care, increased use of telehealth (a significant focus early in the pandemic), and avoiding care for less severe alcohol-related complications because of lingering concerns about exposure to COVID-19 in health care settings reported early in the pandemic. Massachusetts experienced a particularly deadly outbreak of COVID-19 in the Soldiers’ Home, a long-term care facility for veterans in Holyoke.²¹

Evidence suggests that in-home consumption of alcohol increased during lockdowns.^8-10 Our results show that during this period hospitalizations for alcohol-related conditions decreased at VABHS, a large urban VA medical system, while alcohol-related deaths increased nationally.¹³ Although this observation is not evidence of causality, these outcomes could be related.

In the 2 decades before the pandemic, alcohol-related deaths increased by about 2% per year.²² From 2019 to 2020, there was a 25% increase that continued through 2021.¹³ Death certificate data often are inaccurate, and it is difficult to determine whether COVID-19 had a substantial contributing role to these deaths, particularly during the initial period when testing was limited or unavailable. Nonetheless, deaths due to alcohol-associated liver disease, overdoses involving alcohol, and alcohol-related traffic fatalities increased by > 10%.^13,23 These trends, along with a decrease in hospitalization for alcohol-related conditions, suggest missed opportunities for intervention with patients experiencing alcohol use disorder.

Limitations

In this study, hospitalizations under observation status were excluded, which could underestimate the total number of hospitalizations related to alcohol. We reasoned that this effect was likely to be small and not substantially different by year. ICD-10 codes were used to identify alcohol-related hospitalizations as any hospitalization with an included ICD-10 code listed as the primary discharge diagnosis code. This also likely underestimated the total number of alcohol-related hospitalizations. An ICD-10 code for COVID-19 was not in widespread use during our study period, which prohibited controlling explicitly for the volume of admissions due to COVID-19. The prelockdown period only contains data from the preceding 3 years, which might not be long enough for secular trends to become apparent. We assumed the population at risk remained constant when in reality, the net movement of patients into and out of VA care during the pandemic likely was more complex but not readily quantifiable. Nonetheless, the large drop in absolute number of alcohol-related hospitalizations is not likely to be sensitive to this change. In the absence of an objective measure of care-seeking behavior, we used the total daily number of hospitalizations as a surrogate for patient propensity to seek care. The total daily number of hospitalizations also reflects changes in physician admitting behavior over time. This allowed explicit modeling of care-seeking behavior as a covariate but does not capture other important determinants such as hospital capacity.

Conclusions

In this interrupted time-series analysis, the daily number of alcohol-related hospitalizations during the initial COVID-19 pandemic–associated lockdown period at VABHS decreased by 80% and remained 28% lower in the postlockdown period compared with the prepandemic baseline. In the context of evidence suggesting that alcohol-related mortality increased during the COVID-19 pandemic, alternate strategies to reach vulnerable individuals are needed. Because of high rates of relapse, hospitalization is an important opportunity to engage patients experiencing alcohol use disorder in treatment through referral to substance use treatment programs and medication-assisted therapy. Considering the reduction in alcohol-related hospitalizations during lockdown, other strategies are needed to ensure comprehensive and longitudinal care for this vulnerable population.

The United States’ initial public health response to the COVID-19 pandemic included containment measures that varied by state but generally required closing or suspending schools, nonessential businesses, and travel (commonly called lockdown).¹ During these periods, hospitalizations for serious and common conditions declined.^2,3 In Massachusetts, a state of emergency was declared on March 10, 2020, which remained in place until May 18, 2020, when a phased reopening of businesses began.

Although the evidence on the mental health impact of containment periods has been mixed, it has been suggested that these measures could lead to increases in alcohol-related hospitalizations.⁴ Social isolation and increased psychosocial and financial stressors raise the risk of relapse among patients with substance use disorders.^5-7 Marketing and survey data from the US and United Kingdom from the early months of the pandemic suggest that in-home alcohol consumption and sales of alcoholic beverages increased, while consumption of alcohol outside the home decreased.^8-10 Other research has shown an increase in the percentage—but not necessarily the absolute number—of emergency department (ED) visits and hospitalizations for alcohol-related diagnoses during periods of containment.^11,12 At least 1 study suggests that alcohol-related deaths increased beginning in the lockdown period and persisting into mid-2021.¹³

Because earlier studies suggest that lockdown periods are associated with increased alcohol consumption and relapse of alcohol use disorder, we hypothesized that the spring 2020 lockdown period in Massachusetts would be associated temporally with an increase in alcohol-related hospitalizations. To evaluate this hypothesis, we examined all hospitalizations in the US Department of Veterans Affairs (VA) Boston Healthcare System (VABHS) before, during, and after this lockdown period. VABHS includes a 160-bed acute care hospital and a 50-bed inpatient psychiatric facility.

Methods

We conducted an interrupted time-series analysis including all inpatient hospitalizations at VABHS from January 1, 2017, to December 31, 2020, to compare the daily number of alcohol-related hospitalizations across 3 exposure groups: prelockdown (the reference group, 1/1/2017-3/9/2020); lockdown (3/10/2020-5/18/2020); and postlockdown (5/19/2020-12/31/2020).

The VA Corporate Data Warehouse at VABHS was queried to identify all hospitalizations on the medical, psychiatry, and neurology services during the study period. Hospitalizations were considered alcohol-related if the International Statistical Classification of Diseases, Tenth Revision (ICD-10) primary diagnosis code (the main reason for hospitalization) was defined as an alcohol-related diagnosis by the VA Centralized Interactive Phenomics Resource (eAppendix 1, available online at doi:10.1278/fp.0404). This database, which has been previously used for COVID-19 research, is a catalog and knowledge-sharing platform of VA electronic health record–based phenotype algorithms, definitions, and metadata that builds on the Million Veteran Program and Cooperative Studies Program.^14,15 Hospitalizations under observation status were excluded.

To examine whether alcohol-related hospitalizations could have been categorized as COVID-19 when the conditions were co-occurring, we identified 244 hospitalizations coded with a primary ICD-10 code for COVID-19 during the lockdown and postlockdown periods. At the time of admission, each hospitalization carries an initial (free text) diagnosis, of which 3 had an initial diagnosis related to alcohol use. The population at risk for alcohol-related hospitalizations was estimated as the number of patients actively engaged in care at the VABHS. This was defined as the number of patients enrolled in VA care who have previously received any VA care; patients who are enrolled but have never received VA care were excluded from the population-at-risk denominator. Population-at-risk data were available for each fiscal year (FY) of the study period (9/30-10/1); the following population-at-risk sizes were used: 38,057 for FY 2017, 38,527 for FY 2018, 39,472 for FY 2019, and 37,893 for FY 2020.

The primary outcome was the daily number of alcohol-related hospitalizations in the prelockdown, lockdown, and postlockdown periods. A sensitivity analysis was performed using an alternate definition of the primary outcome using a broader set of alcohol-related ICD-10 codes (eAppendix 2, available online at doi:10.1278/fp.0404).

Statistical Analysis

To visually examine hospitalization trends during the study period, we generated a smoothed time-series plot of the 7-day moving average of the daily number of all-cause hospitalizations and the daily number of alcohol-related hospitalizations from January 1, 2017, to December 31, 2020. We used multivariable regression to model the daily number of alcohol-related hospitalizations over prelockdown (the reference group), lockdown, and postlockdown. In addition to the exposure, we included the following covariates in our model: day of the week, calendar date (to account for secular trends), and harmonic polynomials of the day of the year (to account for seasonal variation).¹⁶

We also examined models that included the daily total number of hospitalizations to account for the reduced likelihood of hospital admission for any reason during the pandemic. We used generalized linear models with a Poisson link to generate rate ratios and corresponding 95% CIs for estimates of the daily number of alcohol-related hospitalizations. We estimated the population incidence of alcohol-related hospitalizations per 100,000 patient-months for the exposure periods using the population denominators previously described. All analyses were performed in Stata 16.1.

Results

During the study period, 27,508 hospitalizations were available for analysis. The 7-day moving average of total daily hospitalizations and total daily alcohol-related hospitalizations over time for the period January 1, 2017, to December 31, 2020, are shown in the Figure.

The incidence of alcohol-related hospitalizations in the population dropped from 72 per 100,000 patient-months to 10 per 100,000 patient-months during the lockdown period and increased to 46 per 100,000 patient-months during the postlockdown period (Table).

Discussion

During the spring 2020 COVID-19 lockdown period in Massachusetts, the daily number of VABHS alcohol-related hospitalizations decreased by nearly 80% compared with the prelockdown period. During the postlockdown period, the daily number of alcohol-related hospitalizations increased but only to 72% of the prelockdown baseline by the end of December 2020. A similar trend was observed for all-cause hospitalizations for the same exposure periods.

These results differ from 2 related studies on the effect of the COVID-19 pandemic on alcohol-related hospitalizations.^10,11 In a retrospective study of ED visits to 4 hospitals in New York City, Schimmel and colleagues reported that from March 1 to 31, 2020 (the initial COVID-19 peak), hospital visits for alcohol withdrawal increased while those for alcohol use decreased.¹⁰ However, these results are reported as a percentage of total ED visits rather than the total number of visits, which are vulnerable to spurious correlation because of concomitant changes in the total number of ED visits. In their study, the absolute number of alcohol-related ED visits did not increase during the initial 2020 COVID-19 peak, and the number of visits for alcohol withdrawal syndrome declined slightly (195 in 2019 and 180 in 2020). However, the percentage of visits increased from 7% to 10% because of a greater decline in total ED visits. This pattern of decline in the number of alcohol-related ED visits, accompanied by an increase in the percentage of alcohol-related ED visits, has been observed in at least 1 nationwide surveillance study.¹⁷ This apparent increase does not reflect an absolute increase in ED visits for alcohol withdrawal syndrome and represents a greater relative decline in visits for other causes during the study period.

Sharma and colleagues reported an increase in the percentage of patients who developed alcohol withdrawal syndrome while hospitalized in Delaware per 1000 hospitalizations during consecutive 2-week periods during the pandemic in 2020 compared with corresponding weeks in 2019.¹¹ The greatest increase occurred during the last 2 weeks of the Delaware stay-at-home order. The Clinical Institute Withdrawal Assessment of Alcohol Scale, revised (CIWA-Ar) score of > 8 was used to define alcohol withdrawal syndrome. The American Society of Addiction Medicine does not recommend using CIWA-Ar to diagnose alcohol withdrawal syndrome because the scale was developed to monitor response to treatment, not to establish a diagnosis.¹⁸

Although the true population incidence of alcohol-related hospitalizations is difficult to estimate because the size of the population at risk (ie, the denominator) often is not known, the total number of hospitalizations is not a reliable surrogate.¹⁹ Individuals hospitalized for nonalcohol causes are no longer at risk for alcohol-related hospitalization.

In our study, we assume the population at risk during the study period is constant and model changes in the absolute number—rather than percentage—of alcohol-related ED visits. These absolute estimates of alcohol-related hospitalizations better reflect the true burden on the health care system and avoid the confounding effect of declining total ED visits and hospitalizations that could lead to artificially increased percentages and spurious correlation.²⁰ The absolute percentage of alcohol-related hospitalizations also decreased during this period; therefore, our results are not sensitive to this approach.

Several factors could have contributed to the decrease in alcohol-related hospitalizations. Our findings suggest that patient likelihood to seek care and clinician threshold to admit patients for alcohol-related conditions are influenced by external factors, in this case, a public health lockdown. Although our data do not inform why hospitalizations did not return to prelockdown levels, our experience suggests that limited bed capacity and longer length of stay might have contributed. Other hypotheses include a shift to outpatient care, increased use of telehealth (a significant focus early in the pandemic), and avoiding care for less severe alcohol-related complications because of lingering concerns about exposure to COVID-19 in health care settings reported early in the pandemic. Massachusetts experienced a particularly deadly outbreak of COVID-19 in the Soldiers’ Home, a long-term care facility for veterans in Holyoke.²¹

Evidence suggests that in-home consumption of alcohol increased during lockdowns.^8-10 Our results show that during this period hospitalizations for alcohol-related conditions decreased at VABHS, a large urban VA medical system, while alcohol-related deaths increased nationally.¹³ Although this observation is not evidence of causality, these outcomes could be related.

In the 2 decades before the pandemic, alcohol-related deaths increased by about 2% per year.²² From 2019 to 2020, there was a 25% increase that continued through 2021.¹³ Death certificate data often are inaccurate, and it is difficult to determine whether COVID-19 had a substantial contributing role to these deaths, particularly during the initial period when testing was limited or unavailable. Nonetheless, deaths due to alcohol-associated liver disease, overdoses involving alcohol, and alcohol-related traffic fatalities increased by > 10%.^13,23 These trends, along with a decrease in hospitalization for alcohol-related conditions, suggest missed opportunities for intervention with patients experiencing alcohol use disorder.

Limitations

In this study, hospitalizations under observation status were excluded, which could underestimate the total number of hospitalizations related to alcohol. We reasoned that this effect was likely to be small and not substantially different by year. ICD-10 codes were used to identify alcohol-related hospitalizations as any hospitalization with an included ICD-10 code listed as the primary discharge diagnosis code. This also likely underestimated the total number of alcohol-related hospitalizations. An ICD-10 code for COVID-19 was not in widespread use during our study period, which prohibited controlling explicitly for the volume of admissions due to COVID-19. The prelockdown period only contains data from the preceding 3 years, which might not be long enough for secular trends to become apparent. We assumed the population at risk remained constant when in reality, the net movement of patients into and out of VA care during the pandemic likely was more complex but not readily quantifiable. Nonetheless, the large drop in absolute number of alcohol-related hospitalizations is not likely to be sensitive to this change. In the absence of an objective measure of care-seeking behavior, we used the total daily number of hospitalizations as a surrogate for patient propensity to seek care. The total daily number of hospitalizations also reflects changes in physician admitting behavior over time. This allowed explicit modeling of care-seeking behavior as a covariate but does not capture other important determinants such as hospital capacity.

Conclusions

In this interrupted time-series analysis, the daily number of alcohol-related hospitalizations during the initial COVID-19 pandemic–associated lockdown period at VABHS decreased by 80% and remained 28% lower in the postlockdown period compared with the prepandemic baseline. In the context of evidence suggesting that alcohol-related mortality increased during the COVID-19 pandemic, alternate strategies to reach vulnerable individuals are needed. Because of high rates of relapse, hospitalization is an important opportunity to engage patients experiencing alcohol use disorder in treatment through referral to substance use treatment programs and medication-assisted therapy. Considering the reduction in alcohol-related hospitalizations during lockdown, other strategies are needed to ensure comprehensive and longitudinal care for this vulnerable population.

Case Presentation. A 23-year-old male U.S. Army veteran with a history of alcohol use disorder and posttraumatic stress disorder (PTSD) presented to the VA Boston Healthcare System (VABHS) West Roxbury campus emergency department (ED) with epigastric abdominal pain in the setting of consuming alcohol. The patient had served in the infantry in Afghanistan during Operation Enduring Freedom. He consumed up to 12 alcoholic drinks per day (both beer and hard liquor) for the past 3 years and had been hospitalized 3 times previously; twice for alcohol detoxification and once for PTSD. He is a former tobacco smoker with fewer than 5 pack-years, he uses marijuana often and does not use IV drugs. In the ED, his physical examination was notable for a heart rate of 130 beats per minute and blood pressure of 161/111 mm Hg. He was alert and oriented and had a mild tremor. The patient was diaphoretic with dry mucous membranes, tenderness to palpation in the epigastrium, and abdominal guarding. A computed tomography (CT) scan of the abdomen revealed acute pancreatitis without necrosis. The patient received 1 L of normal saline and was admitted to the medical ward for presumed alcoholic pancreatitis.

► Rahul Ganatra, MD, MPH, Chief Medical Resident, VABHS and Beth Israel Deaconess Medical Center. Dr. Weber, we care for many young people who drink more than they should and almost none of them end up with alcoholic pancreatitis. What are the relevant risk factors that make individuals like this patient more susceptible to alcoholic pancreatitis?

►Horst Christian Weber, MD, Gastroenterology Service, VABHS, and Assistant Professor of Medicine, Boston University School of Medicine. While we don’t have a good understanding of the precise mechanism of alcoholic pancreatitis, we do know that in the U.S., alcohol consumption is responsible for about one-third of all cases.¹ Acute pancreatitis in general may present with a wide range of disease severity. It is the most common cause of gastrointestinal-related hospitalization,² and the mortality of hospital inpatients with pancreatitis is about 5%.^3,4 Therefore, acute pancreatitis represents a prevalent condition with a critical impact on morbidity and mortality. Alcoholic pancreatitis typically occurs after many years of heavy alcohol use, not after a single drinking

► Dr. Ganatra. At this point, the chemistry laboratory paged the admitting resident with the notification that the patient’s blood was grossly lipemic. Ultracentrifugation was performed to separate the lipid layer and his laboratory values result (Table). Notable abnormalities included polycythemia with a hemoglobin of 17.4 g/dL, hyponatremia with a sodium of 129 mmol/L, normal renal function, elevated aspartate aminotransferase (AST) and alanine aminotransferase (ALT) (AST 258 IU/L and ALT 153 IU/L, respectively), hyperbilirubinemia with a total bilirubin of 2.7 mg/dL, and a serum alcohol level of 147 mg/dL. Due to anticipated requirement for a higher level of care, the patient was transferred to the Medical Intensive Care Unit (MICU).

Dr. Breu, can you help us interpret this patient’s numerous laboratory abnormalities? Without yet having the triglyceride level available, how does the fact that the patient’s blood was lipemic affect our interpretation of his labs? What further workup is warranted?

► Anthony Breu, MD, Medical Service, VABHS, Assistant Professor of Medicine, Harvard Medical School. First, the positive alcohol level confirms a recent ingestion. Second, he has elevated transaminases with the AST greater than the ALT, which is consistent with alcoholic liver disease. While the initial assumption is that this patient has alcohol-induced pancreatitis, the elevations in bilirubin and alkaline phosphatase may suggest gallstone pancreatitis, and the lipemic appearing serum could suggest triglyceride-mediated pancreatitis. If the patient does have elevated triglyceride levels, the sodium level may indicate pseudohyponatremia, a laboratory artifact seen if a dilution step is used. To further evaluate the patient, I would obtain a triglyceride level and a right upper quadrant ultrasound. Direct ion-selective electrode analysis of the sodium level can be done with a device used to measure blood gases to exclude pseudohyponatremia.

► Dr. Ganatra. A right upper quadrant ultrasound was obtained in the MICU, which showed hepatic steatosis and hepatomegaly to 19 cm, but no evidence of biliary obstruction by stones or sludge. The common bile duct measured 3.2 mm in diameter. A triglyceride level returned above assay at > 3,392 mg/dL. A review of the medical record revealed a triglyceride level of 105 mg/dL 16 months prior. The Gastroenterology Department was consulted.

Dr. Weber, we now have 2 etiologies for pancreatitis in this patient: alcohol and hypertriglyceridemia. How do each cause pancreatitis? Is it possible to determine in this case which one is the more likely driver?

► Dr. Weber. The mechanism for alcohol-induced pancreatitis is not fully known, but there are several hypotheses. One is that alcohol may increase the synthesis or activation of pancreatic digestive enzymes.⁶ Another is that metabolites of alcohol are directly toxic to the pancreas.⁶ Based on the epidemiologic observation that alcoholic pancreatitis usually happens in long-standing users, all we can say is that it is not very likely to be the effect of an acute insult. For hypertriglyceridemic pancreatitis, we believe the injury is due to the toxic effect of free fatty acids in the pancreas liberated by lipolysis of triglycerides by pancreatic lipases. Higher triglycerides are associated with higher risk, suggesting a dose-response relationship: This risk is not greatly increased until triglycerides exceed 500 mg/dL; above 1,000 mg/dL, the risk is about 5%, and above 2,000 mg/dL, the risk is between 10% and 20%.⁷ In summary, we cannot really determine whether the alcohol or the triglycerides are the main cause of his pancreatitis, but given his markedly elevated triglycerides, he should be treated for hypertriglyceridemic pancreatitis.

►Dr. Ganatra. Dr. Breu, regardless of the underlying etiology, this patient requires treatment. What does the literature suggest as the best course of action regarding crystalloid administration in patients with acute pancreatitis?

►Dr. Breu. There are 2 issues to discuss regarding IV fluids in acute pancreatitis: choice of crystalloid and rate of administration. For the choice of IV fluid, lactated Ringer solution (LR) may be preferred over normal saline (NS). There are both pathophysiologic and evidence-based rationales for this choice. As Dr. Weber alluded to, trypsinogen activation is an important step in the pathogenesis of acute pancreatitis and requires a low pH compartment. As most clinicians have experienced, NS may cause a metabolic acidosis; however, the use of LR may mitigate this. A 2011 randomized clinical trial showed that patients who received LR had less systemic inflammatory response syndrome (SIRS) and lower C-reactive protein (CRP) levels at 24 hours compared with patients who received NS.⁸ While these are surrogate outcomes, they, along with the theoretical basis, suggest LR is preferred.

Regarding rate, the key is fast and early.⁹ In my experience, internists often underdose IV rehydration within the first 12 to 24 hours, fail to change the rate based on clinical response, and leave patients on high rates too long. In a patient like this, a rate of 350 cc/h is a reasonable place to start. But, one must reassess response (ie, ensure there is a decrease in hematocrit and/or blood urea nitrogen) every 6 hours and increase the rate as needed. After the first 24 to 48 hours have passed, the rate should be lowered.

►Dr. Ganatra. The patient received 2 mg of IV hydromorphone and a 2 L bolus of LR. This was followed by a continuous infusion of LR at 200 cc/h. Dr. Weber, apart from the standard therapies for pancreatitis, what are our treatment options in hypertriglyceridemic pancreatitis?

►Dr. Weber. In the acute setting, IV insulin with or without dextrose is the most extensively studied therapy. Insulin rapidly decreases triglyceride levels by activating lipoprotein lipase and inhibiting hormone- sensitive lipase. The net effect is reduction in serum triglycerides available to be hydrolyzed to free fatty acids in the pancreas.⁷ For severe cases (ie, where acute pancreatitis is accompanied by hypocalcemia, lactic acidosis or a markedly elevated lipase), apheresis with therapeutic plasma exchange to more rapidly reduce triglyceride concentration is the preferred therapy. The goal is to reduce triglycerides to levels

►Dr. Ganatra. Due to the possibility that the patient would require apheresis, which was not available at the VABHS West Roxbury campus, the patient was transferred to an affiliate hospital. The patient was started on 10% dextrose at 300 cc/h and an IV insulin infusion. His triglycerides fell to < 500 mg/dL over the subsequent 48 hours, and ultimately, apheresis was not required. Enteral nutrition by nasogastric (NG) tube was initiated on hospital day 6. The patient’s hospital course was notable for acute respiratory distress syndrome that required intubation for 7 days, hyperbilirubinemia (with a peak bilirubin of 10.5 mg/dL), acute kidney injury (with a peak creatinine 4.7 mg/dL), fever without an identified infectious source, alcohol withdrawal syndrome that required phenobarbital, and delirium. Nine days later, he was transferred back to the VABHS West Roxbury campus. His condition stabilized, and he was transferred to the medical floor. On hospital day 14, the patient’s mental status improved, and he began tolerating oral nutrition.

Dr. Breu, over the years, the standard of care regarding when to start enteral nutrition in pancreatitis has changed considerably. This patient received enteral nutrition via NG tube but also had periods of being NPO (nothing by mouth) for up to 6 days. What is the current best practice for timing of initiating enteral nutrition in acute pancreatitis?

►Dr. Breu. It is true that the standard of care has changed and continues to evolve. Many decades ago, patients with acute pancreatitis would routinely undergo NG tube suction to reduce delivery of gastric contents to the duodenum, thereby decreasing pancreas activation, allowing it to rest.¹¹ The NG tube also allowed for decompression of any ileus that had formed. Beginning in the 1970s, several clinical trials were performed, showing that NG tube suction was no better than simply making the patient NPO.^12,13 More recently, we have begun to move toward earlier feeding. Again, there is a pathophysiologic rationale (bowel rest is associated with intestinal atrophy, predisposing to bacterial translocation and resulting infectious complications) and increasing evidence supporting this practice.⁹ Even in severe pancreatitis, hunger may be used to initiate oral intake.¹⁴

►Dr. Weber. Organ failure in the acute setting can occur due to activation of cytokine cascades and the systemic inflammatory response syndrome and is described by clinical and radiologic criteria called the Atlanta Classification.¹⁵ Apart from organ failure, the most serious complications of acute pancreatitis are necrosis of pancreatic tissue leading to walled-off pancreatic necrosis and the formation of peripancreatic fluid collections and pseudocysts, which occur in about 15% of patients with acute pancreatitis. These complications are serious because they can become infected, which portends a higher mortality and in some cases require surgical resection.

Other complications of acute pancreatitis include pseudoaneurysm formation, which is when a vessel bleeds into a pancreatic pseudocyst, and thromboses of the splenic, portal, or mesenteric veins. Thrombotic complications may occur in up to half of patients with pancreatic necrosis but are uncommon without some degree of necrosis.¹⁶ No necrosis was noted on this patient’s initial CT scan, so the probability of thrombosis is low. Also, as it takes several weeks for pseudocyst formation to occur, a bleeding pseudoaneurysm is unlikely at this early stage. Therefore, a complication of pancreatitis is unlikely in this patient, and evaluation for other causes of abdominal pain should be considered.

►Dr. Ganatra. A noncontrast CT of the abdomen and pelvis was obtained and revealed no evidence of complications or other acute pathology. His pain was managed conservatively, and hemoglobin remained stable. Over the next 5 days, the patient’s symptoms gradually resolved, his oral intake improved, and he was discharged home on gemfibrozil 600 mg twice daily 19 days after admission. He declined psychiatry follow-up for his PTSD, and after discharge he did not keep his scheduled gastroenterology (GI) follow-up appointment. Four months later, the patient presented again with epigastric abdominal pain similar to his initial presentation. The patient had resumed drinking, stating that “alcohol is the only thing that helps [with the PTSD].” He had not been taking the gemfibrozil. He was admitted with a recurrent episode of pancreatitis; however, his triglycerides on admission were 119 mg/dL.

Dr. Weber, this patient’s triglycerides declined rapidly over a period of just 4 months with questionable adherence to gemfibrozil. However, he was admitted again with another episode of pancreatitis, this time in the setting of alcohol use alone without markedly elevated triglycerides. What do we know about recurrence risk for pancreatitis? Are some etiologies of pancreatitis more likely to present with recurrent attacks than are others?

►Dr. Weber. The rate of recurrence following an episode of acute pancreatitis varies according to the cause, but in general, about 20% to 30% of patients will experience a recurrence, and 5% to 10% will go on to develop chronic pancreatitis.¹⁷ Alcoholic pancreatitis does carry a higher risk of recurrence than pancreatitis due to other causes; the risk is as high as 50%. Not surprisingly, recurrence of acute pancreatitis increases risk for development of chronic pancreatitis. As this patient is a smoker, it is worth noting that smoking potentiates pancreatic damage from alcohol and increases the risk for both recurrent and chronic pancreatitis.⁵

►Dr. Ganatra. The patient was treated with IV hydromorphone and IV LR at 350 cc/h. Oral nutrition was begun immediately. He manifested no organ dysfunction, and his symptoms improved over the course of 48 hours. He was discharged home with psychiatry and GI follow-up scheduled. Dr. Breu and Dr. Weber, how should we counsel this patient to reduce his risk of recurrent attacks of pancreatitis in the future, and what options do we have for pharmacotherapy to decrease his risk?

►Dr. Breu. I’ll let Dr. Weber comment on mitigating the risk of hypertriglyceride-induced pancreatitis and reserve my comments to pharmacotherapy in alcohol use disorder. This patient may be a candidate for naltrexone therapy, either in oral or intramuscular formulations. Both have been showed to reduce the risk of returning to heavy drinking and may be particularly beneficial in those with a family history.^18,19 Acamprosate is also an option.

►Dr. Weber. Data on recurrence risk in hypertriglyceridemic pancreatitis are limited, but there are case reports suggesting that a fatty diet and alcohol use are implicated in recurrence.²⁰ I would counsel the patient on lifestyle modifications that are known to reduce this risk. I agree with Dr. Breu that devoting our efforts to helping him reduce or eliminate his alcohol consumption is the single most important thing we can do to reduce his risk for recurrent attacks. Since the patient reports that he drinks alcohol in order to cope with his PTSD, establishing care with a mental health provider to address this is of the utmost importance. In addition, smoking cessation and promoting medication adherence with gemfibrozil will also reduce risk for future episodes, but continued alcohol use is his strongest risk factor.

►Dr. Ganatra. After discharge, the patient engaged with outpatient psychiatry and GI. He still reports feeling that alcohol is the only thing that alleviates his PTSD and anxiety symptoms. He is not currently interested in pharmacotherapy for cessation of alcohol use.

Acknowledgments
The authors thank Ivana Jankovic, MD, Matthew Lewis Chase, MD, Christopher Worsham, MD, Lakshmana Swamy, MD.

Case Presentation. A 23-year-old male U.S. Army veteran with a history of alcohol use disorder and posttraumatic stress disorder (PTSD) presented to the VA Boston Healthcare System (VABHS) West Roxbury campus emergency department (ED) with epigastric abdominal pain in the setting of consuming alcohol. The patient had served in the infantry in Afghanistan during Operation Enduring Freedom. He consumed up to 12 alcoholic drinks per day (both beer and hard liquor) for the past 3 years and had been hospitalized 3 times previously; twice for alcohol detoxification and once for PTSD. He is a former tobacco smoker with fewer than 5 pack-years, he uses marijuana often and does not use IV drugs. In the ED, his physical examination was notable for a heart rate of 130 beats per minute and blood pressure of 161/111 mm Hg. He was alert and oriented and had a mild tremor. The patient was diaphoretic with dry mucous membranes, tenderness to palpation in the epigastrium, and abdominal guarding. A computed tomography (CT) scan of the abdomen revealed acute pancreatitis without necrosis. The patient received 1 L of normal saline and was admitted to the medical ward for presumed alcoholic pancreatitis.

► Rahul Ganatra, MD, MPH, Chief Medical Resident, VABHS and Beth Israel Deaconess Medical Center. Dr. Weber, we care for many young people who drink more than they should and almost none of them end up with alcoholic pancreatitis. What are the relevant risk factors that make individuals like this patient more susceptible to alcoholic pancreatitis?

►Horst Christian Weber, MD, Gastroenterology Service, VABHS, and Assistant Professor of Medicine, Boston University School of Medicine. While we don’t have a good understanding of the precise mechanism of alcoholic pancreatitis, we do know that in the U.S., alcohol consumption is responsible for about one-third of all cases.¹ Acute pancreatitis in general may present with a wide range of disease severity. It is the most common cause of gastrointestinal-related hospitalization,² and the mortality of hospital inpatients with pancreatitis is about 5%.^3,4 Therefore, acute pancreatitis represents a prevalent condition with a critical impact on morbidity and mortality. Alcoholic pancreatitis typically occurs after many years of heavy alcohol use, not after a single drinking

► Dr. Ganatra. At this point, the chemistry laboratory paged the admitting resident with the notification that the patient’s blood was grossly lipemic. Ultracentrifugation was performed to separate the lipid layer and his laboratory values result (Table). Notable abnormalities included polycythemia with a hemoglobin of 17.4 g/dL, hyponatremia with a sodium of 129 mmol/L, normal renal function, elevated aspartate aminotransferase (AST) and alanine aminotransferase (ALT) (AST 258 IU/L and ALT 153 IU/L, respectively), hyperbilirubinemia with a total bilirubin of 2.7 mg/dL, and a serum alcohol level of 147 mg/dL. Due to anticipated requirement for a higher level of care, the patient was transferred to the Medical Intensive Care Unit (MICU).

Dr. Breu, can you help us interpret this patient’s numerous laboratory abnormalities? Without yet having the triglyceride level available, how does the fact that the patient’s blood was lipemic affect our interpretation of his labs? What further workup is warranted?

► Anthony Breu, MD, Medical Service, VABHS, Assistant Professor of Medicine, Harvard Medical School. First, the positive alcohol level confirms a recent ingestion. Second, he has elevated transaminases with the AST greater than the ALT, which is consistent with alcoholic liver disease. While the initial assumption is that this patient has alcohol-induced pancreatitis, the elevations in bilirubin and alkaline phosphatase may suggest gallstone pancreatitis, and the lipemic appearing serum could suggest triglyceride-mediated pancreatitis. If the patient does have elevated triglyceride levels, the sodium level may indicate pseudohyponatremia, a laboratory artifact seen if a dilution step is used. To further evaluate the patient, I would obtain a triglyceride level and a right upper quadrant ultrasound. Direct ion-selective electrode analysis of the sodium level can be done with a device used to measure blood gases to exclude pseudohyponatremia.

► Dr. Ganatra. A right upper quadrant ultrasound was obtained in the MICU, which showed hepatic steatosis and hepatomegaly to 19 cm, but no evidence of biliary obstruction by stones or sludge. The common bile duct measured 3.2 mm in diameter. A triglyceride level returned above assay at > 3,392 mg/dL. A review of the medical record revealed a triglyceride level of 105 mg/dL 16 months prior. The Gastroenterology Department was consulted.

Dr. Weber, we now have 2 etiologies for pancreatitis in this patient: alcohol and hypertriglyceridemia. How do each cause pancreatitis? Is it possible to determine in this case which one is the more likely driver?

► Dr. Weber. The mechanism for alcohol-induced pancreatitis is not fully known, but there are several hypotheses. One is that alcohol may increase the synthesis or activation of pancreatic digestive enzymes.⁶ Another is that metabolites of alcohol are directly toxic to the pancreas.⁶ Based on the epidemiologic observation that alcoholic pancreatitis usually happens in long-standing users, all we can say is that it is not very likely to be the effect of an acute insult. For hypertriglyceridemic pancreatitis, we believe the injury is due to the toxic effect of free fatty acids in the pancreas liberated by lipolysis of triglycerides by pancreatic lipases. Higher triglycerides are associated with higher risk, suggesting a dose-response relationship: This risk is not greatly increased until triglycerides exceed 500 mg/dL; above 1,000 mg/dL, the risk is about 5%, and above 2,000 mg/dL, the risk is between 10% and 20%.⁷ In summary, we cannot really determine whether the alcohol or the triglycerides are the main cause of his pancreatitis, but given his markedly elevated triglycerides, he should be treated for hypertriglyceridemic pancreatitis.

►Dr. Ganatra. Dr. Breu, regardless of the underlying etiology, this patient requires treatment. What does the literature suggest as the best course of action regarding crystalloid administration in patients with acute pancreatitis?

►Dr. Breu. There are 2 issues to discuss regarding IV fluids in acute pancreatitis: choice of crystalloid and rate of administration. For the choice of IV fluid, lactated Ringer solution (LR) may be preferred over normal saline (NS). There are both pathophysiologic and evidence-based rationales for this choice. As Dr. Weber alluded to, trypsinogen activation is an important step in the pathogenesis of acute pancreatitis and requires a low pH compartment. As most clinicians have experienced, NS may cause a metabolic acidosis; however, the use of LR may mitigate this. A 2011 randomized clinical trial showed that patients who received LR had less systemic inflammatory response syndrome (SIRS) and lower C-reactive protein (CRP) levels at 24 hours compared with patients who received NS.⁸ While these are surrogate outcomes, they, along with the theoretical basis, suggest LR is preferred.

Regarding rate, the key is fast and early.⁹ In my experience, internists often underdose IV rehydration within the first 12 to 24 hours, fail to change the rate based on clinical response, and leave patients on high rates too long. In a patient like this, a rate of 350 cc/h is a reasonable place to start. But, one must reassess response (ie, ensure there is a decrease in hematocrit and/or blood urea nitrogen) every 6 hours and increase the rate as needed. After the first 24 to 48 hours have passed, the rate should be lowered.

►Dr. Ganatra. The patient received 2 mg of IV hydromorphone and a 2 L bolus of LR. This was followed by a continuous infusion of LR at 200 cc/h. Dr. Weber, apart from the standard therapies for pancreatitis, what are our treatment options in hypertriglyceridemic pancreatitis?

►Dr. Weber. In the acute setting, IV insulin with or without dextrose is the most extensively studied therapy. Insulin rapidly decreases triglyceride levels by activating lipoprotein lipase and inhibiting hormone- sensitive lipase. The net effect is reduction in serum triglycerides available to be hydrolyzed to free fatty acids in the pancreas.⁷ For severe cases (ie, where acute pancreatitis is accompanied by hypocalcemia, lactic acidosis or a markedly elevated lipase), apheresis with therapeutic plasma exchange to more rapidly reduce triglyceride concentration is the preferred therapy. The goal is to reduce triglycerides to levels

►Dr. Ganatra. Due to the possibility that the patient would require apheresis, which was not available at the VABHS West Roxbury campus, the patient was transferred to an affiliate hospital. The patient was started on 10% dextrose at 300 cc/h and an IV insulin infusion. His triglycerides fell to < 500 mg/dL over the subsequent 48 hours, and ultimately, apheresis was not required. Enteral nutrition by nasogastric (NG) tube was initiated on hospital day 6. The patient’s hospital course was notable for acute respiratory distress syndrome that required intubation for 7 days, hyperbilirubinemia (with a peak bilirubin of 10.5 mg/dL), acute kidney injury (with a peak creatinine 4.7 mg/dL), fever without an identified infectious source, alcohol withdrawal syndrome that required phenobarbital, and delirium. Nine days later, he was transferred back to the VABHS West Roxbury campus. His condition stabilized, and he was transferred to the medical floor. On hospital day 14, the patient’s mental status improved, and he began tolerating oral nutrition.

Dr. Breu, over the years, the standard of care regarding when to start enteral nutrition in pancreatitis has changed considerably. This patient received enteral nutrition via NG tube but also had periods of being NPO (nothing by mouth) for up to 6 days. What is the current best practice for timing of initiating enteral nutrition in acute pancreatitis?

►Dr. Breu. It is true that the standard of care has changed and continues to evolve. Many decades ago, patients with acute pancreatitis would routinely undergo NG tube suction to reduce delivery of gastric contents to the duodenum, thereby decreasing pancreas activation, allowing it to rest.¹¹ The NG tube also allowed for decompression of any ileus that had formed. Beginning in the 1970s, several clinical trials were performed, showing that NG tube suction was no better than simply making the patient NPO.^12,13 More recently, we have begun to move toward earlier feeding. Again, there is a pathophysiologic rationale (bowel rest is associated with intestinal atrophy, predisposing to bacterial translocation and resulting infectious complications) and increasing evidence supporting this practice.⁹ Even in severe pancreatitis, hunger may be used to initiate oral intake.¹⁴

►Dr. Weber. Organ failure in the acute setting can occur due to activation of cytokine cascades and the systemic inflammatory response syndrome and is described by clinical and radiologic criteria called the Atlanta Classification.¹⁵ Apart from organ failure, the most serious complications of acute pancreatitis are necrosis of pancreatic tissue leading to walled-off pancreatic necrosis and the formation of peripancreatic fluid collections and pseudocysts, which occur in about 15% of patients with acute pancreatitis. These complications are serious because they can become infected, which portends a higher mortality and in some cases require surgical resection.

Other complications of acute pancreatitis include pseudoaneurysm formation, which is when a vessel bleeds into a pancreatic pseudocyst, and thromboses of the splenic, portal, or mesenteric veins. Thrombotic complications may occur in up to half of patients with pancreatic necrosis but are uncommon without some degree of necrosis.¹⁶ No necrosis was noted on this patient’s initial CT scan, so the probability of thrombosis is low. Also, as it takes several weeks for pseudocyst formation to occur, a bleeding pseudoaneurysm is unlikely at this early stage. Therefore, a complication of pancreatitis is unlikely in this patient, and evaluation for other causes of abdominal pain should be considered.

►Dr. Ganatra. A noncontrast CT of the abdomen and pelvis was obtained and revealed no evidence of complications or other acute pathology. His pain was managed conservatively, and hemoglobin remained stable. Over the next 5 days, the patient’s symptoms gradually resolved, his oral intake improved, and he was discharged home on gemfibrozil 600 mg twice daily 19 days after admission. He declined psychiatry follow-up for his PTSD, and after discharge he did not keep his scheduled gastroenterology (GI) follow-up appointment. Four months later, the patient presented again with epigastric abdominal pain similar to his initial presentation. The patient had resumed drinking, stating that “alcohol is the only thing that helps [with the PTSD].” He had not been taking the gemfibrozil. He was admitted with a recurrent episode of pancreatitis; however, his triglycerides on admission were 119 mg/dL.

Dr. Weber, this patient’s triglycerides declined rapidly over a period of just 4 months with questionable adherence to gemfibrozil. However, he was admitted again with another episode of pancreatitis, this time in the setting of alcohol use alone without markedly elevated triglycerides. What do we know about recurrence risk for pancreatitis? Are some etiologies of pancreatitis more likely to present with recurrent attacks than are others?

►Dr. Weber. The rate of recurrence following an episode of acute pancreatitis varies according to the cause, but in general, about 20% to 30% of patients will experience a recurrence, and 5% to 10% will go on to develop chronic pancreatitis.¹⁷ Alcoholic pancreatitis does carry a higher risk of recurrence than pancreatitis due to other causes; the risk is as high as 50%. Not surprisingly, recurrence of acute pancreatitis increases risk for development of chronic pancreatitis. As this patient is a smoker, it is worth noting that smoking potentiates pancreatic damage from alcohol and increases the risk for both recurrent and chronic pancreatitis.⁵

►Dr. Ganatra. The patient was treated with IV hydromorphone and IV LR at 350 cc/h. Oral nutrition was begun immediately. He manifested no organ dysfunction, and his symptoms improved over the course of 48 hours. He was discharged home with psychiatry and GI follow-up scheduled. Dr. Breu and Dr. Weber, how should we counsel this patient to reduce his risk of recurrent attacks of pancreatitis in the future, and what options do we have for pharmacotherapy to decrease his risk?

►Dr. Breu. I’ll let Dr. Weber comment on mitigating the risk of hypertriglyceride-induced pancreatitis and reserve my comments to pharmacotherapy in alcohol use disorder. This patient may be a candidate for naltrexone therapy, either in oral or intramuscular formulations. Both have been showed to reduce the risk of returning to heavy drinking and may be particularly beneficial in those with a family history.^18,19 Acamprosate is also an option.

►Dr. Weber. Data on recurrence risk in hypertriglyceridemic pancreatitis are limited, but there are case reports suggesting that a fatty diet and alcohol use are implicated in recurrence.²⁰ I would counsel the patient on lifestyle modifications that are known to reduce this risk. I agree with Dr. Breu that devoting our efforts to helping him reduce or eliminate his alcohol consumption is the single most important thing we can do to reduce his risk for recurrent attacks. Since the patient reports that he drinks alcohol in order to cope with his PTSD, establishing care with a mental health provider to address this is of the utmost importance. In addition, smoking cessation and promoting medication adherence with gemfibrozil will also reduce risk for future episodes, but continued alcohol use is his strongest risk factor.

►Dr. Ganatra. After discharge, the patient engaged with outpatient psychiatry and GI. He still reports feeling that alcohol is the only thing that alleviates his PTSD and anxiety symptoms. He is not currently interested in pharmacotherapy for cessation of alcohol use.

Acknowledgments
The authors thank Ivana Jankovic, MD, Matthew Lewis Chase, MD, Christopher Worsham, MD, Lakshmana Swamy, MD.

Case Presentation. A 23-year-old male U.S. Army veteran with a history of alcohol use disorder and posttraumatic stress disorder (PTSD) presented to the VA Boston Healthcare System (VABHS) West Roxbury campus emergency department (ED) with epigastric abdominal pain in the setting of consuming alcohol. The patient had served in the infantry in Afghanistan during Operation Enduring Freedom. He consumed up to 12 alcoholic drinks per day (both beer and hard liquor) for the past 3 years and had been hospitalized 3 times previously; twice for alcohol detoxification and once for PTSD. He is a former tobacco smoker with fewer than 5 pack-years, he uses marijuana often and does not use IV drugs. In the ED, his physical examination was notable for a heart rate of 130 beats per minute and blood pressure of 161/111 mm Hg. He was alert and oriented and had a mild tremor. The patient was diaphoretic with dry mucous membranes, tenderness to palpation in the epigastrium, and abdominal guarding. A computed tomography (CT) scan of the abdomen revealed acute pancreatitis without necrosis. The patient received 1 L of normal saline and was admitted to the medical ward for presumed alcoholic pancreatitis.

► Rahul Ganatra, MD, MPH, Chief Medical Resident, VABHS and Beth Israel Deaconess Medical Center. Dr. Weber, we care for many young people who drink more than they should and almost none of them end up with alcoholic pancreatitis. What are the relevant risk factors that make individuals like this patient more susceptible to alcoholic pancreatitis?

►Horst Christian Weber, MD, Gastroenterology Service, VABHS, and Assistant Professor of Medicine, Boston University School of Medicine. While we don’t have a good understanding of the precise mechanism of alcoholic pancreatitis, we do know that in the U.S., alcohol consumption is responsible for about one-third of all cases.¹ Acute pancreatitis in general may present with a wide range of disease severity. It is the most common cause of gastrointestinal-related hospitalization,² and the mortality of hospital inpatients with pancreatitis is about 5%.^3,4 Therefore, acute pancreatitis represents a prevalent condition with a critical impact on morbidity and mortality. Alcoholic pancreatitis typically occurs after many years of heavy alcohol use, not after a single drinking

► Dr. Ganatra. At this point, the chemistry laboratory paged the admitting resident with the notification that the patient’s blood was grossly lipemic. Ultracentrifugation was performed to separate the lipid layer and his laboratory values result (Table). Notable abnormalities included polycythemia with a hemoglobin of 17.4 g/dL, hyponatremia with a sodium of 129 mmol/L, normal renal function, elevated aspartate aminotransferase (AST) and alanine aminotransferase (ALT) (AST 258 IU/L and ALT 153 IU/L, respectively), hyperbilirubinemia with a total bilirubin of 2.7 mg/dL, and a serum alcohol level of 147 mg/dL. Due to anticipated requirement for a higher level of care, the patient was transferred to the Medical Intensive Care Unit (MICU).

Dr. Breu, can you help us interpret this patient’s numerous laboratory abnormalities? Without yet having the triglyceride level available, how does the fact that the patient’s blood was lipemic affect our interpretation of his labs? What further workup is warranted?

► Anthony Breu, MD, Medical Service, VABHS, Assistant Professor of Medicine, Harvard Medical School. First, the positive alcohol level confirms a recent ingestion. Second, he has elevated transaminases with the AST greater than the ALT, which is consistent with alcoholic liver disease. While the initial assumption is that this patient has alcohol-induced pancreatitis, the elevations in bilirubin and alkaline phosphatase may suggest gallstone pancreatitis, and the lipemic appearing serum could suggest triglyceride-mediated pancreatitis. If the patient does have elevated triglyceride levels, the sodium level may indicate pseudohyponatremia, a laboratory artifact seen if a dilution step is used. To further evaluate the patient, I would obtain a triglyceride level and a right upper quadrant ultrasound. Direct ion-selective electrode analysis of the sodium level can be done with a device used to measure blood gases to exclude pseudohyponatremia.

► Dr. Ganatra. A right upper quadrant ultrasound was obtained in the MICU, which showed hepatic steatosis and hepatomegaly to 19 cm, but no evidence of biliary obstruction by stones or sludge. The common bile duct measured 3.2 mm in diameter. A triglyceride level returned above assay at > 3,392 mg/dL. A review of the medical record revealed a triglyceride level of 105 mg/dL 16 months prior. The Gastroenterology Department was consulted.

Dr. Weber, we now have 2 etiologies for pancreatitis in this patient: alcohol and hypertriglyceridemia. How do each cause pancreatitis? Is it possible to determine in this case which one is the more likely driver?

► Dr. Weber. The mechanism for alcohol-induced pancreatitis is not fully known, but there are several hypotheses. One is that alcohol may increase the synthesis or activation of pancreatic digestive enzymes.⁶ Another is that metabolites of alcohol are directly toxic to the pancreas.⁶ Based on the epidemiologic observation that alcoholic pancreatitis usually happens in long-standing users, all we can say is that it is not very likely to be the effect of an acute insult. For hypertriglyceridemic pancreatitis, we believe the injury is due to the toxic effect of free fatty acids in the pancreas liberated by lipolysis of triglycerides by pancreatic lipases. Higher triglycerides are associated with higher risk, suggesting a dose-response relationship: This risk is not greatly increased until triglycerides exceed 500 mg/dL; above 1,000 mg/dL, the risk is about 5%, and above 2,000 mg/dL, the risk is between 10% and 20%.⁷ In summary, we cannot really determine whether the alcohol or the triglycerides are the main cause of his pancreatitis, but given his markedly elevated triglycerides, he should be treated for hypertriglyceridemic pancreatitis.

►Dr. Ganatra. Dr. Breu, regardless of the underlying etiology, this patient requires treatment. What does the literature suggest as the best course of action regarding crystalloid administration in patients with acute pancreatitis?

►Dr. Breu. There are 2 issues to discuss regarding IV fluids in acute pancreatitis: choice of crystalloid and rate of administration. For the choice of IV fluid, lactated Ringer solution (LR) may be preferred over normal saline (NS). There are both pathophysiologic and evidence-based rationales for this choice. As Dr. Weber alluded to, trypsinogen activation is an important step in the pathogenesis of acute pancreatitis and requires a low pH compartment. As most clinicians have experienced, NS may cause a metabolic acidosis; however, the use of LR may mitigate this. A 2011 randomized clinical trial showed that patients who received LR had less systemic inflammatory response syndrome (SIRS) and lower C-reactive protein (CRP) levels at 24 hours compared with patients who received NS.⁸ While these are surrogate outcomes, they, along with the theoretical basis, suggest LR is preferred.

Regarding rate, the key is fast and early.⁹ In my experience, internists often underdose IV rehydration within the first 12 to 24 hours, fail to change the rate based on clinical response, and leave patients on high rates too long. In a patient like this, a rate of 350 cc/h is a reasonable place to start. But, one must reassess response (ie, ensure there is a decrease in hematocrit and/or blood urea nitrogen) every 6 hours and increase the rate as needed. After the first 24 to 48 hours have passed, the rate should be lowered.

►Dr. Ganatra. The patient received 2 mg of IV hydromorphone and a 2 L bolus of LR. This was followed by a continuous infusion of LR at 200 cc/h. Dr. Weber, apart from the standard therapies for pancreatitis, what are our treatment options in hypertriglyceridemic pancreatitis?

►Dr. Weber. In the acute setting, IV insulin with or without dextrose is the most extensively studied therapy. Insulin rapidly decreases triglyceride levels by activating lipoprotein lipase and inhibiting hormone- sensitive lipase. The net effect is reduction in serum triglycerides available to be hydrolyzed to free fatty acids in the pancreas.⁷ For severe cases (ie, where acute pancreatitis is accompanied by hypocalcemia, lactic acidosis or a markedly elevated lipase), apheresis with therapeutic plasma exchange to more rapidly reduce triglyceride concentration is the preferred therapy. The goal is to reduce triglycerides to levels

►Dr. Ganatra. Due to the possibility that the patient would require apheresis, which was not available at the VABHS West Roxbury campus, the patient was transferred to an affiliate hospital. The patient was started on 10% dextrose at 300 cc/h and an IV insulin infusion. His triglycerides fell to < 500 mg/dL over the subsequent 48 hours, and ultimately, apheresis was not required. Enteral nutrition by nasogastric (NG) tube was initiated on hospital day 6. The patient’s hospital course was notable for acute respiratory distress syndrome that required intubation for 7 days, hyperbilirubinemia (with a peak bilirubin of 10.5 mg/dL), acute kidney injury (with a peak creatinine 4.7 mg/dL), fever without an identified infectious source, alcohol withdrawal syndrome that required phenobarbital, and delirium. Nine days later, he was transferred back to the VABHS West Roxbury campus. His condition stabilized, and he was transferred to the medical floor. On hospital day 14, the patient’s mental status improved, and he began tolerating oral nutrition.

Dr. Breu, over the years, the standard of care regarding when to start enteral nutrition in pancreatitis has changed considerably. This patient received enteral nutrition via NG tube but also had periods of being NPO (nothing by mouth) for up to 6 days. What is the current best practice for timing of initiating enteral nutrition in acute pancreatitis?

►Dr. Breu. It is true that the standard of care has changed and continues to evolve. Many decades ago, patients with acute pancreatitis would routinely undergo NG tube suction to reduce delivery of gastric contents to the duodenum, thereby decreasing pancreas activation, allowing it to rest.¹¹ The NG tube also allowed for decompression of any ileus that had formed. Beginning in the 1970s, several clinical trials were performed, showing that NG tube suction was no better than simply making the patient NPO.^12,13 More recently, we have begun to move toward earlier feeding. Again, there is a pathophysiologic rationale (bowel rest is associated with intestinal atrophy, predisposing to bacterial translocation and resulting infectious complications) and increasing evidence supporting this practice.⁹ Even in severe pancreatitis, hunger may be used to initiate oral intake.¹⁴

►Dr. Weber. Organ failure in the acute setting can occur due to activation of cytokine cascades and the systemic inflammatory response syndrome and is described by clinical and radiologic criteria called the Atlanta Classification.¹⁵ Apart from organ failure, the most serious complications of acute pancreatitis are necrosis of pancreatic tissue leading to walled-off pancreatic necrosis and the formation of peripancreatic fluid collections and pseudocysts, which occur in about 15% of patients with acute pancreatitis. These complications are serious because they can become infected, which portends a higher mortality and in some cases require surgical resection.

Other complications of acute pancreatitis include pseudoaneurysm formation, which is when a vessel bleeds into a pancreatic pseudocyst, and thromboses of the splenic, portal, or mesenteric veins. Thrombotic complications may occur in up to half of patients with pancreatic necrosis but are uncommon without some degree of necrosis.¹⁶ No necrosis was noted on this patient’s initial CT scan, so the probability of thrombosis is low. Also, as it takes several weeks for pseudocyst formation to occur, a bleeding pseudoaneurysm is unlikely at this early stage. Therefore, a complication of pancreatitis is unlikely in this patient, and evaluation for other causes of abdominal pain should be considered.

►Dr. Ganatra. A noncontrast CT of the abdomen and pelvis was obtained and revealed no evidence of complications or other acute pathology. His pain was managed conservatively, and hemoglobin remained stable. Over the next 5 days, the patient’s symptoms gradually resolved, his oral intake improved, and he was discharged home on gemfibrozil 600 mg twice daily 19 days after admission. He declined psychiatry follow-up for his PTSD, and after discharge he did not keep his scheduled gastroenterology (GI) follow-up appointment. Four months later, the patient presented again with epigastric abdominal pain similar to his initial presentation. The patient had resumed drinking, stating that “alcohol is the only thing that helps [with the PTSD].” He had not been taking the gemfibrozil. He was admitted with a recurrent episode of pancreatitis; however, his triglycerides on admission were 119 mg/dL.

Dr. Weber, this patient’s triglycerides declined rapidly over a period of just 4 months with questionable adherence to gemfibrozil. However, he was admitted again with another episode of pancreatitis, this time in the setting of alcohol use alone without markedly elevated triglycerides. What do we know about recurrence risk for pancreatitis? Are some etiologies of pancreatitis more likely to present with recurrent attacks than are others?

►Dr. Weber. The rate of recurrence following an episode of acute pancreatitis varies according to the cause, but in general, about 20% to 30% of patients will experience a recurrence, and 5% to 10% will go on to develop chronic pancreatitis.¹⁷ Alcoholic pancreatitis does carry a higher risk of recurrence than pancreatitis due to other causes; the risk is as high as 50%. Not surprisingly, recurrence of acute pancreatitis increases risk for development of chronic pancreatitis. As this patient is a smoker, it is worth noting that smoking potentiates pancreatic damage from alcohol and increases the risk for both recurrent and chronic pancreatitis.⁵

►Dr. Ganatra. The patient was treated with IV hydromorphone and IV LR at 350 cc/h. Oral nutrition was begun immediately. He manifested no organ dysfunction, and his symptoms improved over the course of 48 hours. He was discharged home with psychiatry and GI follow-up scheduled. Dr. Breu and Dr. Weber, how should we counsel this patient to reduce his risk of recurrent attacks of pancreatitis in the future, and what options do we have for pharmacotherapy to decrease his risk?

►Dr. Breu. I’ll let Dr. Weber comment on mitigating the risk of hypertriglyceride-induced pancreatitis and reserve my comments to pharmacotherapy in alcohol use disorder. This patient may be a candidate for naltrexone therapy, either in oral or intramuscular formulations. Both have been showed to reduce the risk of returning to heavy drinking and may be particularly beneficial in those with a family history.^18,19 Acamprosate is also an option.

►Dr. Weber. Data on recurrence risk in hypertriglyceridemic pancreatitis are limited, but there are case reports suggesting that a fatty diet and alcohol use are implicated in recurrence.²⁰ I would counsel the patient on lifestyle modifications that are known to reduce this risk. I agree with Dr. Breu that devoting our efforts to helping him reduce or eliminate his alcohol consumption is the single most important thing we can do to reduce his risk for recurrent attacks. Since the patient reports that he drinks alcohol in order to cope with his PTSD, establishing care with a mental health provider to address this is of the utmost importance. In addition, smoking cessation and promoting medication adherence with gemfibrozil will also reduce risk for future episodes, but continued alcohol use is his strongest risk factor.

►Dr. Ganatra. After discharge, the patient engaged with outpatient psychiatry and GI. He still reports feeling that alcohol is the only thing that alleviates his PTSD and anxiety symptoms. He is not currently interested in pharmacotherapy for cessation of alcohol use.

Acknowledgments
The authors thank Ivana Jankovic, MD, Matthew Lewis Chase, MD, Christopher Worsham, MD, Lakshmana Swamy, MD.