Clinical Review

A 39-year-old black woman, gravida 1, para 0, with an intrauterine pregnancy of 34 weeks and three days (according to last menstrual period and nine-week ultrasound) presented to her Ob-Gyn office for a routine prenatal visit. She was found to have an elevated blood pressure with new onset of 2+ proteinuria. The patient was sent to the labor and delivery unit at the adjoining hospital for serial blood pressure readings, laboratory work, and fetal monitoring.

The patient’s previous medical history was limited to sinusitis. She was taking no prescription medications, and her only listed allergy was to pineapple. Initial lab studies revealed elevations in liver enzymes, lactate dehydrogenase (LDH), uric acid, and serum creatinine, as well as thrombocytopenia (see Table 1^1-5). She also had a critically low blood glucose level, which conflicted with a normal follow-up reading.

At this point, the patient was thought to have HELLP syndrome⁶ (ie, hemolysis, elevated liver enzymes, low platelet count), or possibly acute fatty liver of pregnancy (AFLP).^2,4,7-11 Additional labs were drawn immediately to confirm or rule out AFLP. These included repeat serum glucose (following a second reading with normal results), a serum ammonia level, prothrombin time (PT), and partial thromboplastin time (PTT). The most reliable values to distinguish AFLP from HELLP are profound hypoglycemia (found in 94% of women with AFLP¹²) and an elevated serum ammonia level.⁴

Given the serious nature of either diagnosis, immediate delivery of the infant was deemed necessary. Because the patient’s cervix was not found favorable for induction, she underwent low-transverse cesarean delivery without complications. She was noted to have essentially normal anatomy with the exception of a small subserosal fibroid posteriorly. Meconium-stained amniotic fluid was present. A male infant was delivered, weighing 5 lb with 1-minute and 5-minute Apgar scores of 8 and 9, respectively.

Postoperatively, the patient remained in the recovery area, where she received intensive monitoring. She experienced fluctuations in blood glucose, ranging from 33 to 144 mg/dL; she was started on 5% dextrose in lactated Ringer’s solution and treated with IV dextrose 50 g. While the patient was in surgical recovery, results from the second set of labs, drawn before surgery, were returned; findings included an elevated ammonia level and an abnormal coagulation panel, including PT of 25.3 sec, PTT of 48.4 sec, and a fibrinogen level of 116 mg/dL, confirming the suspected diagnosis of AFLP.

Magnesium sulfate, which had been started immediately postop, was discontinued on confirmation of the diagnosis of AFLP. The patient was initially somnolent as a result of general anesthesia but gradually returned to a fully normal sensorium by early morning on postop day 1. Postoperatively, the patient’s hemoglobin was found to be low (8.6 g/dL; reference range, 13.5 to 18.5 g/dL), so she was transfused with two units of packed red blood cells (PRBCs) and given fresh frozen plasma (FFP) to correct this coagulopathy. The patient’s platelets were also low at 82,000/mm³ (reference range, 140,000 to 340,000/mm³).

On postop day 1, the patient’s serum creatinine rose to 4.2 mg/dL and her total bilirubin increased to 14.4 mg/dL (reference ranges, 0.6 to 1.2 mg/dL and < 1.0 mg/dL, respectively). Given the multiple systems affected by AFLP and the need for intensive supportive care, the patient was transferred to the ICU.

On her arrival at the ICU, the patient’s vital signs were initially stable, and she was alert and oriented. However, within the next few hours, she became hypotensive and encephalopathic. She required aggressive fluid resuscitation and multiple transfusions of PRBCs and FFP due to persistent anemia and coagulopathy. Her vital signs were stabilized, but she continued to need blood transfusions.

Postop day 2, the patient became less responsive and was soon unable to follow commands or speak clearly. Her breathing remained stable with just 3 L of oxygen by nasal cannula, but in order to prevent aspiration and in consideration of a postoperative ileus, it was necessary to place a nasogastric tube with low intermittent suction. This produced a bloody return, but no intervention other than close monitoring and transfusion was performed at that time.

Abdominal ultrasound showed ascites and mild left-sided hydronephrosis with no gallstones. The common bile duct measured 3 mm in diameter.

Although liver biopsy is considered the gold standard for a confirmed diagnosis of AFLP,^13,14 this procedure was contraindicated by the patient’s coagulopathy. Concern was also expressed by one consultant that the patient might have thrombotic thrombocytopenic purpura (TTP) in addition to AFLP. TTP can manifest with similar findings, such as anemia, thrombocytopenia, neurologic symptoms, and renal abnormalities, but usually fever is involved, and the patient was afebrile. A catheter was placed for hemodialysis and therapeutic plasma exchange (TPE). Given that TTP-associated mortality is significantly decreased by use of TPE,¹⁵ this intervention was deemed prudent. The patient underwent TPE on three consecutive days, postop days 2 through 4.

The patient’s mental status began to improve, and by postop day 6, she was able to follow commands and engage in brief conversations. By postop day 9, she had returned almost completely to her baseline mental status.

The patient’s liver function test results and total bilirubin, ammonia, and creatinine levels all improved over the first few postoperative days but began to rise again by day 6. In response to worsening renal and hepatic functioning, the decision was made on postop day 9 to transfer the patient to a hospital with liver transplantation capabilities, should this procedure become necessary.

Discussion
AFLP is a rare condition specific to pregnancy, affecting 1/7,000 to 1/20,000 pregnancies. Due to the low incidence of this disease, randomized controlled trials to study it are not possible. Instead, clinicians must learn either from individual case studies or from retrospective syntheses of cases reported over time.^1,2,7 Fortunately, the wealth of information gleaned over the past 30 years has significantly reduced AFLP-associated maternal and fetal mortality and morbidity rates. In the 1980s, maternal and fetal mortality rates as high as 85% were reported.³ Worldwide, maternal mortality associated with AFLP has decreased significantly to 7% to 18%, whereas the fetal mortality rate has fallen to between 9% and 23%.^1,16,17

Common trends among women who have developed AFLP include nulliparity, multiparity, and advanced maternal age. One retrospective study of 57 women who had developed AFLP revealed that 35 cases (61%) involved first-time pregnancies. It also showed that 10 (18%) of the women had twins, and 14 (25%) were older than 35.² In another study of 35 cases of AFLP, 40% of the women were nulliparous, and 11.4% were multiparous, including one triplet gestation.¹² In a third, smaller study, 80% of women affected by AFLP were multiparous.¹⁰ Currently, there is no known evidence linking any maternal behavior to development of AFLP.

Presentation
Women who present with AFLP often experience vague, nonspecific symptoms, leading to misdiagnosis or delayed diagnosis. Objective measurements, including physical exam findings, laboratory studies, and other diagnostic tests, will help with a diagnosis. The most frequent initial symptoms are nausea and vomiting (in 70% of patients) and abdominal pain (50% to 80%), epigastric or right upper-quadrant.³ Other common symptoms include fatigue, malaise, anorexia, weight gain, polyuria, and polydipsia.^2,3,9,18,19

Because the presenting symptoms in AFLP can be vague, clinicians should complete a thorough physical exam to differentiate accurately among conditions associated with pregnancy. Physical signs present in women with AFLP can include jaundice, ascites, edema, confusion, abdominal tenderness, and fever. More severe cases can present with multisystem involvement, including acute renal failure, gastrointestinal bleeding, pancreatitis, coagulopathy, and hepatic encephalopathy.^3,4,9,18

Diagnostic Tests
Relevant laboratory tests include a complete blood count (CBC), liver studies, chemistry, coagulation studies, and urinalysis (see Table 1). Viral causes should be ruled out by way of a hepatitis panel.³ In AFLP, the CBC may show elevated white blood cells, decreased hemoglobin and hematocrit, and decreased platelets. Liver studies show elevated hepatic aminotransferase, bilirubin, LDH, and ammonia levels. Chemistry results show elevated blood urea nitrogen and creatinine, and decreased blood glucose. Coagulation factors are affected, and prolonged PTT, decreased fibrinogen, and proteinurea may also be found.⁹

Though invasive and not often necessary^4,13 (and not possible for the case patient), the definitive diagnostic test for AFLP is liver biopsy.^13,14 Biopsy reveals a microvesicular fatty infiltration of the hepatocytes as minute fat droplets surrounding a centrally located nucleus. These fatty infiltrates stain with oil red O, specific for fat. Inflammation is present in 50% of cases. There may also be a picture similar to cholestasis with bile thrombi or deposits within the hepatocytes.²⁰

Due to the risk for hemorrhage and the critical status of women with AFLP, biopsy is often not possible. Ultrasonography may show increased echogenicity; CT may show decreased or diffuse attenuation in the liver. These imaging studies, though possibly helpful in severe cases, often yield false-negative results.^3,20

In the absence of another explanation for the patient’s symptoms, the Swansea criteria are used for diagnosis of AFLP.¹ Six or more of the following criteria must be present to confirm this diagnosis: vomiting, abdominal pain, polydipsia or polyuria, encephalopathy, leukocytosis, elevated bilirubin, elevated liver enzymes, elevated ammonia, hypoglycemia, renal dysfunction, coagulopathy, elevated uric acid, ascites on ultrasound, and microvesicular steatosis on liver biopsy.^1,2,5

Pathophysiology
Normal functions of the liver include metabolism, protein synthesis, and manufacturing of blood coagulation proteins. These functions are disturbed in the presence of AFLP. Thus, women with this disease experience signs and symptoms related directly to the dysfunction of these processes.^20-22

Disturbances in the hepatocytes due to excess fatty acids impair the liver’s ability to convert unconjugated bilirubin into conjugated bilirubin, causing plasma levels of unconjugated bilirubin to rise. This increase in bilirubin explains the jaundiced appearance of women with AFLP. AFLP is often thought to occur in conjunction with preeclampsia in many, but not all, patients. Thrombocytopenia in these patients is felt to be secondary to peripheral vascular consumption. Conjugated bilirubin levels may also be increased due to decreased flow of conjugated bilirubin into the common bile duct.²¹

Another liver function that is disrupted is that of glycogen storage and conversion to glucose, and the liver’s ability to convert nutrients into glycogen is also impaired. Decreased storage of glycogen, along with the liver’s inability to break down previously stored glycogen, causes a decrease in serum glucose levels. Women with AFLP often require treatment with IV dextrose in response to marked hypoglycemia.^16,21,23

The liver dysfunction associated with AFLP reduces adequate production of clotting factors and coagulation proteins. Thrombocytopenia, elevated clotting times, and bleeding are all problems seen in AFLP. Mild to moderate elevations in serum aminotransferases and elevated LDH also occur in patients with AFLP.^23,24

Genetic Factor
There is little known about the etiology of AFLP, although recent data point to a genetic component that was found in as many as 62% of mothers in one study and in 25% of infants in another study.^20-22 Fatty acid oxidation (FAO) is one of the processes of hepatic mitochondria, a process that relies on several enzymes. When FAO is interrupted, fatty acids are deposited in the liver cells, as seen in histologic studies of AFLP.^25,26 The common thread in women with this disease is a mutation in one of the enzymes needed for FAO. This enzyme is the long-chain 3-hydroxyacyl-CoA dehydrogenase. Deficiencies in this enzyme are common in mothers with AFLP and their infants.^{3,16,20,23,27}

Differential Diagnosis
Several complications of pregnancy that involve the liver may, on presentation, mimic AFLP.^{16,20,23,24,28} The most common are hyperemesis gravidarum and intrahepatic cholestasis of pregnancy²³ (see Table 2^{16,20,23,24,28}); others are preeclampsia/eclampsia and HELLP syndrome. It is important to distinguish between the signs and symptoms associated with each of these disorders in order to provide the most effective treatment. Hepatitis serologies are important in the differential diagnosis when liver enzyme levels are exceptionally high.^4,16,22,28

Treatment
The most effective treatment for AFLP is delivery of the infant; often, this alone causes the signs and symptoms of AFLP to resolve.^8,21,27,29 In two of three cases in a small study by Aso et al,⁸ early delivery of the fetus led to complete resolution of symptoms and return to normal liver function. One of these patients was sent home four days after delivery; the other, 14 days later. Other patients may require more invasive treatment and support.⁸

Management in the ICU is often required to provide appropriate supportive care to the mother after delivery. Acute respiratory distress syndrome, pancreatitis, hemorrhage, encephalopathy, renal failure, and continual liver failure are among the severe complications associated with AFLP.^4,8,10 Many women require intubation, dialysis, fluid resuscitation, blood product transfusion, and vasopressor therapy.^3,8,11 Prophylactic antibiotics, IV steroids, and glucose may all be required in the supportive care and recovery of a mother with AFLP.^3,8,11

TPE has also been useful in instances of severe complications.1,3,6 In one retrospective study, Martin et al¹ recommended administration of TPE in patients with AFLP under the following circumstances:

(1) Deteriorating central nervous system abnormalities, such as sensorium changes or coma;

(2) Persistent coagulopathy requiring continued and aggressive blood product support with plasma, red cells, and/or cryoprecipitate;

(3) Advanced renal dysfunction that compromised fluid management;

(4) Progressive cardiopulmonary compromise; and/or

(5) Ongoing fluid management concerns, including significant ascites, edema, anuria/oliguria, and/or fluid overload.¹

In rare cases, liver transplantation is needed in patients with AFLP. Westbrook et al¹⁸ reviewed 54 cases of liver disease in pregnancy in one UK hospital between 1997 and 2008. Of these, six patients with encephalopathy or elevated lactate were listed for liver transplant, including just one with a diagnosis of AFLP. This woman never actually underwent transplant but recovered in response to medical management alone.¹⁸ According to data reported in June 2011 by the Organ Procurement and Transplantation Network,³⁰ liver transplantation was needed in only three US patients with AFLP between 2000 and 2011. Further retrospective studies on outcomes from transplant versus medical management should be considered to guide future decision making involving this invasive therapy.

The Case Patient
This 39-year-old patient presented during a routine prenatal visit with proteinuria and hypertension, possibly indicative of preeclampsia. Because of the serious nature of this potential diagnosis in pregnancy, she was admitted for monitoring and further testing. Although the diagnosis of AFLP was not confirmed until later, the patient’s preliminary lab studies showed elevated liver enzymes and low platelet counts, signifying the need for prompt intervention and delivery of the infant. At this point, the patient met criteria for HELLP syndrome, but AFLP was suspected after the initial finding of profound hypoglycemia led to further testing.

As an older mother experiencing pregnancy for the first time, this patient fit the profile for AFLP. She initially responded well after delivery of her infant but continued to experience complications. On the days that the patient was treated with TPE, her total bilirubin and liver enzymes were at their lowest. Perhaps this treatment should be considered in more cases of AFLP.

The patient was transferred to a hospital with liver transplantation capabilities, but she ultimately recovered without undergoing transplant.

Conclusion
For the primary obstetric care provider, being aware of the possible complications associated with pregnancy is important. Though uncommon, AFLP is a serious complication that should be ruled out in women who present with vague symptoms such as nausea, vomiting, and abdominal pain in the third trimester of pregnancy. The reduction in AFLP-associated morbidity and mortality during the past 20 years is a direct result of increased early recognition and therapeutic delivery.

Referral to a maternal fetal medicine specialist, gastroenterologist, hematologist, and/or nephrologist may be necessary and appropriate in the management of a woman with AFLP. Further study is indicated for use of TPE in more severe cases of AFLP, particularly in women affected by persistent thrombocytopenia and anemia.

The author would like to thank C. Leanne Browning, MD, obstetrics/gynecology, for her invaluable guidance and advice on this project.

References
1. Martin JN Jr, Briery CM, Rose CH, et al. Postpartum plasma exchange as adjunctive therapy for severe acute fatty liver of pregnancy. J Clin Apher. 2009;23(4):138-143.

2. Knight M, Nelson-Piercy C, Kurinczuk JJ; UK Obstetric Surveillance System. A prospective national study of acute fatty liver of pregnancy in the UK. Gut. 2008;57(7):951-956.

3. Barsoom MJ, Tierney BJ. Acute fatty liver of pregnancy (2011). http://emedicine.medscape.com/article/1562425-overview. Accessed January 21, 2013.

4. Ko HH, Yoshida E. Acute fatty liver of pregnancy. Can J Gastroenterol. 2006;20(1):25-30.

5. Rathi U, Bapat M, Rathi P, Abraham P. Effect of liver disease on maternal and fetal outcome: a prospective study. Indian J Gastroenterol. 2007;26(2):59-63.

6. Myers L. Postpartum plasma exchange in a woman with suspected thrombotic thrombocytopenic purpura (TTP) vs hemolysis, elevated liver enzymes, and low platelet syndrome (HELLP): a case study. Nephrol Nurs J. 2010;37(4):399-402.

7. Vigil-de Gracia P. Acute fatty liver and HELLP syndrome: two distinct pregnancy disorders. Int J Gynaecol Obstet. 2001;73(3):215-220.

8. Aso K, Hojo S, Yumoto Y, et al. Three cases of acute fatty liver of pregnancy: postpartum clinical course depends on interval between onset of symptoms and termination of pregnancy. J Matern Fetal Neonatal Med. 2010;23(9):1047-1049.

9. Wei Q, Zhang L, Liu X. Clinical diagnosis and treatment of acute fatty liver of pregnancy: a literature review and 11 new cases. J Obstet Gynaecol Res. 2010;36(4):751-756.

10. Barber MA, Eguiluz I, Martin A, et al. Acute fatty liver of pregnancy: analysis of five consecutive cases from a tertiary centre. J Obstet Gynaecol. 2010;30(3):241-243.

11. Ajayi AO, Alao MO. Case report: acute fatty liver of pregnancy in a 30-year-old Nigerian primigravida. Niger J Clin Pract. 2008;11(4):389-391.

12. Vigíl-de Gracia P, Montufar-Rueda C. Acute fatty liver of pregnancy: diagnosis, treatment, and outcome based on 35 consecutive cases. J Matern Fetal Neonatal Med. 2011;24(9):1143-1146.

13. Dey M, Reema K. Acute fatty liver of pregnancy. N Am J Med Sci. 2012;4(11):611-612.

14. Castro MA, Goodwin TM, Shaw KJ, et al. Disseminated intravascular coagulation and antithrombin III depression in acute fatty liver of pregnancy. Am J Obstet Gynecol. 1996;174(1 pt 1):211-216.

15. Altuntas F, Aydogdu I, Kabukcu S, et al. Therapeutic plasma exchange for the treatment of thrombotic thrombocytopenic purpura: a retrospective multicenter study. Transfus Apher Sci. 2007;36(1):57-67.

16. Hay JE. Liver disease in pregnancy. Hepatology. 2008;47(3):1067-1076.

17. Wand S, Waeschle RM, Von Ahsen N, et al. Acute fatty liver failure due to acute fatty liver of pregnancy. Minerva Anesthesiol. 2012;78(4):503-506.

18. Westbrook RH, Yeoman AD, Joshi D, et al. Outcomes of severe pregnancy-related liver disease: refining the role of transplantation. Am J Transplant. 2010;10(11):2520-2526.

19. Fesenmeier MF, Coppage KH, Lambers DS, et al. Acute fatty liver of pregnancy in 3 tertiary care centers. Am J Obstet Gynecol. 2005;192(5):1416-1419.

20. Bacq Y. Liver diseases unique to pregnancy: a 2010 update. Clin Res Hepatol Gastroenterol. 2011;35(3):182-193.

21. Huether SE. Alterations of digestive function. In: McCance KL, Huether SE, eds. Pathophysiology: The Biologic Basis for Disease in Adults and Children. 6th ed. St. Louis, MO: Mosby; 2009:1452-1515.

22. Huether SE. Structure and function of the digestive system. In: McCance KL, Huether SE, eds. Pathophysiology: The Biologic Basis for Disease in Adults and Children. 6th ed. St. Louis, MO: Mosby; 2009:1420-1451.

23. Schutt VA, Minuk GY. Liver diseases unique to pregnancy. Best Pract Res Clin Gastroenterol. 2007;21(5):771-792.

24. Pan C, Perumalswami PV. Pregnancy-related liver diseases. Clin Liver Dis. 2011;15(1):199-208.

25. Ibdah JA. Acute fatty liver of pregnancy: an update on pathogenesis and clinical implications. World J Gastroenterol. 2006;12(46):7397-7404.

26. Browning MF, Levy HL, Wilkins-Haug LE, et al. Fetal fatty acid oxidation defects and maternal liver disease in pregnancy. Obstet Gynecol. 2006;107(1):115-120.

27. Dekker RR, Schutte JM, Stekelenburg J, et al. Maternal mortality and severe maternal morbidity from acute fatty liver of pregnancy in the Netherlands. Eur J Obstet Gynecol Reprod Biol. 2011;157(1):27-31.

28. Lee NM, Brady CW. Liver disease in pregnancy. World J Gastroenterol. 2009;15(8):897-906.

29. Vora KS, Shah VR, Parikh GP. Acute fatty liver of pregnancy: a case report of an uncommon disease. Indian J Crit Care Med. 2009;13(1):34-36.

30. Organ Procurement and Transplantation Network, Scientific Registry of Transplant Recipients. OPTN/SRTR 2011 Annual Data Report: Liver. http://srtr.transplant.hrsa.gov/annual_reports/2011/pdf/03_%20liver_12.pdf. Accessed January 18, 2013.

A 39-year-old black woman, gravida 1, para 0, with an intrauterine pregnancy of 34 weeks and three days (according to last menstrual period and nine-week ultrasound) presented to her Ob-Gyn office for a routine prenatal visit. She was found to have an elevated blood pressure with new onset of 2+ proteinuria. The patient was sent to the labor and delivery unit at the adjoining hospital for serial blood pressure readings, laboratory work, and fetal monitoring.

The patient’s previous medical history was limited to sinusitis. She was taking no prescription medications, and her only listed allergy was to pineapple. Initial lab studies revealed elevations in liver enzymes, lactate dehydrogenase (LDH), uric acid, and serum creatinine, as well as thrombocytopenia (see Table 1^1-5). She also had a critically low blood glucose level, which conflicted with a normal follow-up reading.

At this point, the patient was thought to have HELLP syndrome⁶ (ie, hemolysis, elevated liver enzymes, low platelet count), or possibly acute fatty liver of pregnancy (AFLP).^2,4,7-11 Additional labs were drawn immediately to confirm or rule out AFLP. These included repeat serum glucose (following a second reading with normal results), a serum ammonia level, prothrombin time (PT), and partial thromboplastin time (PTT). The most reliable values to distinguish AFLP from HELLP are profound hypoglycemia (found in 94% of women with AFLP¹²) and an elevated serum ammonia level.⁴

Given the serious nature of either diagnosis, immediate delivery of the infant was deemed necessary. Because the patient’s cervix was not found favorable for induction, she underwent low-transverse cesarean delivery without complications. She was noted to have essentially normal anatomy with the exception of a small subserosal fibroid posteriorly. Meconium-stained amniotic fluid was present. A male infant was delivered, weighing 5 lb with 1-minute and 5-minute Apgar scores of 8 and 9, respectively.

Postoperatively, the patient remained in the recovery area, where she received intensive monitoring. She experienced fluctuations in blood glucose, ranging from 33 to 144 mg/dL; she was started on 5% dextrose in lactated Ringer’s solution and treated with IV dextrose 50 g. While the patient was in surgical recovery, results from the second set of labs, drawn before surgery, were returned; findings included an elevated ammonia level and an abnormal coagulation panel, including PT of 25.3 sec, PTT of 48.4 sec, and a fibrinogen level of 116 mg/dL, confirming the suspected diagnosis of AFLP.

Magnesium sulfate, which had been started immediately postop, was discontinued on confirmation of the diagnosis of AFLP. The patient was initially somnolent as a result of general anesthesia but gradually returned to a fully normal sensorium by early morning on postop day 1. Postoperatively, the patient’s hemoglobin was found to be low (8.6 g/dL; reference range, 13.5 to 18.5 g/dL), so she was transfused with two units of packed red blood cells (PRBCs) and given fresh frozen plasma (FFP) to correct this coagulopathy. The patient’s platelets were also low at 82,000/mm³ (reference range, 140,000 to 340,000/mm³).

On postop day 1, the patient’s serum creatinine rose to 4.2 mg/dL and her total bilirubin increased to 14.4 mg/dL (reference ranges, 0.6 to 1.2 mg/dL and < 1.0 mg/dL, respectively). Given the multiple systems affected by AFLP and the need for intensive supportive care, the patient was transferred to the ICU.

On her arrival at the ICU, the patient’s vital signs were initially stable, and she was alert and oriented. However, within the next few hours, she became hypotensive and encephalopathic. She required aggressive fluid resuscitation and multiple transfusions of PRBCs and FFP due to persistent anemia and coagulopathy. Her vital signs were stabilized, but she continued to need blood transfusions.

Postop day 2, the patient became less responsive and was soon unable to follow commands or speak clearly. Her breathing remained stable with just 3 L of oxygen by nasal cannula, but in order to prevent aspiration and in consideration of a postoperative ileus, it was necessary to place a nasogastric tube with low intermittent suction. This produced a bloody return, but no intervention other than close monitoring and transfusion was performed at that time.

Abdominal ultrasound showed ascites and mild left-sided hydronephrosis with no gallstones. The common bile duct measured 3 mm in diameter.

Although liver biopsy is considered the gold standard for a confirmed diagnosis of AFLP,^13,14 this procedure was contraindicated by the patient’s coagulopathy. Concern was also expressed by one consultant that the patient might have thrombotic thrombocytopenic purpura (TTP) in addition to AFLP. TTP can manifest with similar findings, such as anemia, thrombocytopenia, neurologic symptoms, and renal abnormalities, but usually fever is involved, and the patient was afebrile. A catheter was placed for hemodialysis and therapeutic plasma exchange (TPE). Given that TTP-associated mortality is significantly decreased by use of TPE,¹⁵ this intervention was deemed prudent. The patient underwent TPE on three consecutive days, postop days 2 through 4.

The patient’s mental status began to improve, and by postop day 6, she was able to follow commands and engage in brief conversations. By postop day 9, she had returned almost completely to her baseline mental status.

The patient’s liver function test results and total bilirubin, ammonia, and creatinine levels all improved over the first few postoperative days but began to rise again by day 6. In response to worsening renal and hepatic functioning, the decision was made on postop day 9 to transfer the patient to a hospital with liver transplantation capabilities, should this procedure become necessary.

Discussion
AFLP is a rare condition specific to pregnancy, affecting 1/7,000 to 1/20,000 pregnancies. Due to the low incidence of this disease, randomized controlled trials to study it are not possible. Instead, clinicians must learn either from individual case studies or from retrospective syntheses of cases reported over time.^1,2,7 Fortunately, the wealth of information gleaned over the past 30 years has significantly reduced AFLP-associated maternal and fetal mortality and morbidity rates. In the 1980s, maternal and fetal mortality rates as high as 85% were reported.³ Worldwide, maternal mortality associated with AFLP has decreased significantly to 7% to 18%, whereas the fetal mortality rate has fallen to between 9% and 23%.^1,16,17

Common trends among women who have developed AFLP include nulliparity, multiparity, and advanced maternal age. One retrospective study of 57 women who had developed AFLP revealed that 35 cases (61%) involved first-time pregnancies. It also showed that 10 (18%) of the women had twins, and 14 (25%) were older than 35.² In another study of 35 cases of AFLP, 40% of the women were nulliparous, and 11.4% were multiparous, including one triplet gestation.¹² In a third, smaller study, 80% of women affected by AFLP were multiparous.¹⁰ Currently, there is no known evidence linking any maternal behavior to development of AFLP.

Presentation
Women who present with AFLP often experience vague, nonspecific symptoms, leading to misdiagnosis or delayed diagnosis. Objective measurements, including physical exam findings, laboratory studies, and other diagnostic tests, will help with a diagnosis. The most frequent initial symptoms are nausea and vomiting (in 70% of patients) and abdominal pain (50% to 80%), epigastric or right upper-quadrant.³ Other common symptoms include fatigue, malaise, anorexia, weight gain, polyuria, and polydipsia.^2,3,9,18,19

Because the presenting symptoms in AFLP can be vague, clinicians should complete a thorough physical exam to differentiate accurately among conditions associated with pregnancy. Physical signs present in women with AFLP can include jaundice, ascites, edema, confusion, abdominal tenderness, and fever. More severe cases can present with multisystem involvement, including acute renal failure, gastrointestinal bleeding, pancreatitis, coagulopathy, and hepatic encephalopathy.^3,4,9,18

Diagnostic Tests
Relevant laboratory tests include a complete blood count (CBC), liver studies, chemistry, coagulation studies, and urinalysis (see Table 1). Viral causes should be ruled out by way of a hepatitis panel.³ In AFLP, the CBC may show elevated white blood cells, decreased hemoglobin and hematocrit, and decreased platelets. Liver studies show elevated hepatic aminotransferase, bilirubin, LDH, and ammonia levels. Chemistry results show elevated blood urea nitrogen and creatinine, and decreased blood glucose. Coagulation factors are affected, and prolonged PTT, decreased fibrinogen, and proteinurea may also be found.⁹

Though invasive and not often necessary^4,13 (and not possible for the case patient), the definitive diagnostic test for AFLP is liver biopsy.^13,14 Biopsy reveals a microvesicular fatty infiltration of the hepatocytes as minute fat droplets surrounding a centrally located nucleus. These fatty infiltrates stain with oil red O, specific for fat. Inflammation is present in 50% of cases. There may also be a picture similar to cholestasis with bile thrombi or deposits within the hepatocytes.²⁰

Due to the risk for hemorrhage and the critical status of women with AFLP, biopsy is often not possible. Ultrasonography may show increased echogenicity; CT may show decreased or diffuse attenuation in the liver. These imaging studies, though possibly helpful in severe cases, often yield false-negative results.^3,20

In the absence of another explanation for the patient’s symptoms, the Swansea criteria are used for diagnosis of AFLP.¹ Six or more of the following criteria must be present to confirm this diagnosis: vomiting, abdominal pain, polydipsia or polyuria, encephalopathy, leukocytosis, elevated bilirubin, elevated liver enzymes, elevated ammonia, hypoglycemia, renal dysfunction, coagulopathy, elevated uric acid, ascites on ultrasound, and microvesicular steatosis on liver biopsy.^1,2,5

Pathophysiology
Normal functions of the liver include metabolism, protein synthesis, and manufacturing of blood coagulation proteins. These functions are disturbed in the presence of AFLP. Thus, women with this disease experience signs and symptoms related directly to the dysfunction of these processes.^20-22

Disturbances in the hepatocytes due to excess fatty acids impair the liver’s ability to convert unconjugated bilirubin into conjugated bilirubin, causing plasma levels of unconjugated bilirubin to rise. This increase in bilirubin explains the jaundiced appearance of women with AFLP. AFLP is often thought to occur in conjunction with preeclampsia in many, but not all, patients. Thrombocytopenia in these patients is felt to be secondary to peripheral vascular consumption. Conjugated bilirubin levels may also be increased due to decreased flow of conjugated bilirubin into the common bile duct.²¹

Another liver function that is disrupted is that of glycogen storage and conversion to glucose, and the liver’s ability to convert nutrients into glycogen is also impaired. Decreased storage of glycogen, along with the liver’s inability to break down previously stored glycogen, causes a decrease in serum glucose levels. Women with AFLP often require treatment with IV dextrose in response to marked hypoglycemia.^16,21,23

The liver dysfunction associated with AFLP reduces adequate production of clotting factors and coagulation proteins. Thrombocytopenia, elevated clotting times, and bleeding are all problems seen in AFLP. Mild to moderate elevations in serum aminotransferases and elevated LDH also occur in patients with AFLP.^23,24

Genetic Factor
There is little known about the etiology of AFLP, although recent data point to a genetic component that was found in as many as 62% of mothers in one study and in 25% of infants in another study.^20-22 Fatty acid oxidation (FAO) is one of the processes of hepatic mitochondria, a process that relies on several enzymes. When FAO is interrupted, fatty acids are deposited in the liver cells, as seen in histologic studies of AFLP.^25,26 The common thread in women with this disease is a mutation in one of the enzymes needed for FAO. This enzyme is the long-chain 3-hydroxyacyl-CoA dehydrogenase. Deficiencies in this enzyme are common in mothers with AFLP and their infants.^{3,16,20,23,27}

Differential Diagnosis
Several complications of pregnancy that involve the liver may, on presentation, mimic AFLP.^{16,20,23,24,28} The most common are hyperemesis gravidarum and intrahepatic cholestasis of pregnancy²³ (see Table 2^{16,20,23,24,28}); others are preeclampsia/eclampsia and HELLP syndrome. It is important to distinguish between the signs and symptoms associated with each of these disorders in order to provide the most effective treatment. Hepatitis serologies are important in the differential diagnosis when liver enzyme levels are exceptionally high.^4,16,22,28

Treatment
The most effective treatment for AFLP is delivery of the infant; often, this alone causes the signs and symptoms of AFLP to resolve.^8,21,27,29 In two of three cases in a small study by Aso et al,⁸ early delivery of the fetus led to complete resolution of symptoms and return to normal liver function. One of these patients was sent home four days after delivery; the other, 14 days later. Other patients may require more invasive treatment and support.⁸

Management in the ICU is often required to provide appropriate supportive care to the mother after delivery. Acute respiratory distress syndrome, pancreatitis, hemorrhage, encephalopathy, renal failure, and continual liver failure are among the severe complications associated with AFLP.^4,8,10 Many women require intubation, dialysis, fluid resuscitation, blood product transfusion, and vasopressor therapy.^3,8,11 Prophylactic antibiotics, IV steroids, and glucose may all be required in the supportive care and recovery of a mother with AFLP.^3,8,11

TPE has also been useful in instances of severe complications.1,3,6 In one retrospective study, Martin et al¹ recommended administration of TPE in patients with AFLP under the following circumstances:

(1) Deteriorating central nervous system abnormalities, such as sensorium changes or coma;

(2) Persistent coagulopathy requiring continued and aggressive blood product support with plasma, red cells, and/or cryoprecipitate;

(3) Advanced renal dysfunction that compromised fluid management;

(4) Progressive cardiopulmonary compromise; and/or

(5) Ongoing fluid management concerns, including significant ascites, edema, anuria/oliguria, and/or fluid overload.¹

In rare cases, liver transplantation is needed in patients with AFLP. Westbrook et al¹⁸ reviewed 54 cases of liver disease in pregnancy in one UK hospital between 1997 and 2008. Of these, six patients with encephalopathy or elevated lactate were listed for liver transplant, including just one with a diagnosis of AFLP. This woman never actually underwent transplant but recovered in response to medical management alone.¹⁸ According to data reported in June 2011 by the Organ Procurement and Transplantation Network,³⁰ liver transplantation was needed in only three US patients with AFLP between 2000 and 2011. Further retrospective studies on outcomes from transplant versus medical management should be considered to guide future decision making involving this invasive therapy.

The Case Patient
This 39-year-old patient presented during a routine prenatal visit with proteinuria and hypertension, possibly indicative of preeclampsia. Because of the serious nature of this potential diagnosis in pregnancy, she was admitted for monitoring and further testing. Although the diagnosis of AFLP was not confirmed until later, the patient’s preliminary lab studies showed elevated liver enzymes and low platelet counts, signifying the need for prompt intervention and delivery of the infant. At this point, the patient met criteria for HELLP syndrome, but AFLP was suspected after the initial finding of profound hypoglycemia led to further testing.

As an older mother experiencing pregnancy for the first time, this patient fit the profile for AFLP. She initially responded well after delivery of her infant but continued to experience complications. On the days that the patient was treated with TPE, her total bilirubin and liver enzymes were at their lowest. Perhaps this treatment should be considered in more cases of AFLP.

The patient was transferred to a hospital with liver transplantation capabilities, but she ultimately recovered without undergoing transplant.

Conclusion
For the primary obstetric care provider, being aware of the possible complications associated with pregnancy is important. Though uncommon, AFLP is a serious complication that should be ruled out in women who present with vague symptoms such as nausea, vomiting, and abdominal pain in the third trimester of pregnancy. The reduction in AFLP-associated morbidity and mortality during the past 20 years is a direct result of increased early recognition and therapeutic delivery.

Referral to a maternal fetal medicine specialist, gastroenterologist, hematologist, and/or nephrologist may be necessary and appropriate in the management of a woman with AFLP. Further study is indicated for use of TPE in more severe cases of AFLP, particularly in women affected by persistent thrombocytopenia and anemia.

The author would like to thank C. Leanne Browning, MD, obstetrics/gynecology, for her invaluable guidance and advice on this project.

References
1. Martin JN Jr, Briery CM, Rose CH, et al. Postpartum plasma exchange as adjunctive therapy for severe acute fatty liver of pregnancy. J Clin Apher. 2009;23(4):138-143.

2. Knight M, Nelson-Piercy C, Kurinczuk JJ; UK Obstetric Surveillance System. A prospective national study of acute fatty liver of pregnancy in the UK. Gut. 2008;57(7):951-956.

3. Barsoom MJ, Tierney BJ. Acute fatty liver of pregnancy (2011). http://emedicine.medscape.com/article/1562425-overview. Accessed January 21, 2013.

4. Ko HH, Yoshida E. Acute fatty liver of pregnancy. Can J Gastroenterol. 2006;20(1):25-30.

5. Rathi U, Bapat M, Rathi P, Abraham P. Effect of liver disease on maternal and fetal outcome: a prospective study. Indian J Gastroenterol. 2007;26(2):59-63.

6. Myers L. Postpartum plasma exchange in a woman with suspected thrombotic thrombocytopenic purpura (TTP) vs hemolysis, elevated liver enzymes, and low platelet syndrome (HELLP): a case study. Nephrol Nurs J. 2010;37(4):399-402.

7. Vigil-de Gracia P. Acute fatty liver and HELLP syndrome: two distinct pregnancy disorders. Int J Gynaecol Obstet. 2001;73(3):215-220.

8. Aso K, Hojo S, Yumoto Y, et al. Three cases of acute fatty liver of pregnancy: postpartum clinical course depends on interval between onset of symptoms and termination of pregnancy. J Matern Fetal Neonatal Med. 2010;23(9):1047-1049.

9. Wei Q, Zhang L, Liu X. Clinical diagnosis and treatment of acute fatty liver of pregnancy: a literature review and 11 new cases. J Obstet Gynaecol Res. 2010;36(4):751-756.

10. Barber MA, Eguiluz I, Martin A, et al. Acute fatty liver of pregnancy: analysis of five consecutive cases from a tertiary centre. J Obstet Gynaecol. 2010;30(3):241-243.

11. Ajayi AO, Alao MO. Case report: acute fatty liver of pregnancy in a 30-year-old Nigerian primigravida. Niger J Clin Pract. 2008;11(4):389-391.

12. Vigíl-de Gracia P, Montufar-Rueda C. Acute fatty liver of pregnancy: diagnosis, treatment, and outcome based on 35 consecutive cases. J Matern Fetal Neonatal Med. 2011;24(9):1143-1146.

13. Dey M, Reema K. Acute fatty liver of pregnancy. N Am J Med Sci. 2012;4(11):611-612.

14. Castro MA, Goodwin TM, Shaw KJ, et al. Disseminated intravascular coagulation and antithrombin III depression in acute fatty liver of pregnancy. Am J Obstet Gynecol. 1996;174(1 pt 1):211-216.

15. Altuntas F, Aydogdu I, Kabukcu S, et al. Therapeutic plasma exchange for the treatment of thrombotic thrombocytopenic purpura: a retrospective multicenter study. Transfus Apher Sci. 2007;36(1):57-67.

16. Hay JE. Liver disease in pregnancy. Hepatology. 2008;47(3):1067-1076.

17. Wand S, Waeschle RM, Von Ahsen N, et al. Acute fatty liver failure due to acute fatty liver of pregnancy. Minerva Anesthesiol. 2012;78(4):503-506.

18. Westbrook RH, Yeoman AD, Joshi D, et al. Outcomes of severe pregnancy-related liver disease: refining the role of transplantation. Am J Transplant. 2010;10(11):2520-2526.

19. Fesenmeier MF, Coppage KH, Lambers DS, et al. Acute fatty liver of pregnancy in 3 tertiary care centers. Am J Obstet Gynecol. 2005;192(5):1416-1419.

20. Bacq Y. Liver diseases unique to pregnancy: a 2010 update. Clin Res Hepatol Gastroenterol. 2011;35(3):182-193.

21. Huether SE. Alterations of digestive function. In: McCance KL, Huether SE, eds. Pathophysiology: The Biologic Basis for Disease in Adults and Children. 6th ed. St. Louis, MO: Mosby; 2009:1452-1515.

22. Huether SE. Structure and function of the digestive system. In: McCance KL, Huether SE, eds. Pathophysiology: The Biologic Basis for Disease in Adults and Children. 6th ed. St. Louis, MO: Mosby; 2009:1420-1451.

23. Schutt VA, Minuk GY. Liver diseases unique to pregnancy. Best Pract Res Clin Gastroenterol. 2007;21(5):771-792.

24. Pan C, Perumalswami PV. Pregnancy-related liver diseases. Clin Liver Dis. 2011;15(1):199-208.

25. Ibdah JA. Acute fatty liver of pregnancy: an update on pathogenesis and clinical implications. World J Gastroenterol. 2006;12(46):7397-7404.

26. Browning MF, Levy HL, Wilkins-Haug LE, et al. Fetal fatty acid oxidation defects and maternal liver disease in pregnancy. Obstet Gynecol. 2006;107(1):115-120.

27. Dekker RR, Schutte JM, Stekelenburg J, et al. Maternal mortality and severe maternal morbidity from acute fatty liver of pregnancy in the Netherlands. Eur J Obstet Gynecol Reprod Biol. 2011;157(1):27-31.

28. Lee NM, Brady CW. Liver disease in pregnancy. World J Gastroenterol. 2009;15(8):897-906.

29. Vora KS, Shah VR, Parikh GP. Acute fatty liver of pregnancy: a case report of an uncommon disease. Indian J Crit Care Med. 2009;13(1):34-36.

30. Organ Procurement and Transplantation Network, Scientific Registry of Transplant Recipients. OPTN/SRTR 2011 Annual Data Report: Liver. http://srtr.transplant.hrsa.gov/annual_reports/2011/pdf/03_%20liver_12.pdf. Accessed January 18, 2013.

A 39-year-old black woman, gravida 1, para 0, with an intrauterine pregnancy of 34 weeks and three days (according to last menstrual period and nine-week ultrasound) presented to her Ob-Gyn office for a routine prenatal visit. She was found to have an elevated blood pressure with new onset of 2+ proteinuria. The patient was sent to the labor and delivery unit at the adjoining hospital for serial blood pressure readings, laboratory work, and fetal monitoring.

The patient’s previous medical history was limited to sinusitis. She was taking no prescription medications, and her only listed allergy was to pineapple. Initial lab studies revealed elevations in liver enzymes, lactate dehydrogenase (LDH), uric acid, and serum creatinine, as well as thrombocytopenia (see Table 1^1-5). She also had a critically low blood glucose level, which conflicted with a normal follow-up reading.

At this point, the patient was thought to have HELLP syndrome⁶ (ie, hemolysis, elevated liver enzymes, low platelet count), or possibly acute fatty liver of pregnancy (AFLP).^2,4,7-11 Additional labs were drawn immediately to confirm or rule out AFLP. These included repeat serum glucose (following a second reading with normal results), a serum ammonia level, prothrombin time (PT), and partial thromboplastin time (PTT). The most reliable values to distinguish AFLP from HELLP are profound hypoglycemia (found in 94% of women with AFLP¹²) and an elevated serum ammonia level.⁴

Given the serious nature of either diagnosis, immediate delivery of the infant was deemed necessary. Because the patient’s cervix was not found favorable for induction, she underwent low-transverse cesarean delivery without complications. She was noted to have essentially normal anatomy with the exception of a small subserosal fibroid posteriorly. Meconium-stained amniotic fluid was present. A male infant was delivered, weighing 5 lb with 1-minute and 5-minute Apgar scores of 8 and 9, respectively.

Postoperatively, the patient remained in the recovery area, where she received intensive monitoring. She experienced fluctuations in blood glucose, ranging from 33 to 144 mg/dL; she was started on 5% dextrose in lactated Ringer’s solution and treated with IV dextrose 50 g. While the patient was in surgical recovery, results from the second set of labs, drawn before surgery, were returned; findings included an elevated ammonia level and an abnormal coagulation panel, including PT of 25.3 sec, PTT of 48.4 sec, and a fibrinogen level of 116 mg/dL, confirming the suspected diagnosis of AFLP.

Magnesium sulfate, which had been started immediately postop, was discontinued on confirmation of the diagnosis of AFLP. The patient was initially somnolent as a result of general anesthesia but gradually returned to a fully normal sensorium by early morning on postop day 1. Postoperatively, the patient’s hemoglobin was found to be low (8.6 g/dL; reference range, 13.5 to 18.5 g/dL), so she was transfused with two units of packed red blood cells (PRBCs) and given fresh frozen plasma (FFP) to correct this coagulopathy. The patient’s platelets were also low at 82,000/mm³ (reference range, 140,000 to 340,000/mm³).

On postop day 1, the patient’s serum creatinine rose to 4.2 mg/dL and her total bilirubin increased to 14.4 mg/dL (reference ranges, 0.6 to 1.2 mg/dL and < 1.0 mg/dL, respectively). Given the multiple systems affected by AFLP and the need for intensive supportive care, the patient was transferred to the ICU.

On her arrival at the ICU, the patient’s vital signs were initially stable, and she was alert and oriented. However, within the next few hours, she became hypotensive and encephalopathic. She required aggressive fluid resuscitation and multiple transfusions of PRBCs and FFP due to persistent anemia and coagulopathy. Her vital signs were stabilized, but she continued to need blood transfusions.

Postop day 2, the patient became less responsive and was soon unable to follow commands or speak clearly. Her breathing remained stable with just 3 L of oxygen by nasal cannula, but in order to prevent aspiration and in consideration of a postoperative ileus, it was necessary to place a nasogastric tube with low intermittent suction. This produced a bloody return, but no intervention other than close monitoring and transfusion was performed at that time.

Abdominal ultrasound showed ascites and mild left-sided hydronephrosis with no gallstones. The common bile duct measured 3 mm in diameter.

Although liver biopsy is considered the gold standard for a confirmed diagnosis of AFLP,^13,14 this procedure was contraindicated by the patient’s coagulopathy. Concern was also expressed by one consultant that the patient might have thrombotic thrombocytopenic purpura (TTP) in addition to AFLP. TTP can manifest with similar findings, such as anemia, thrombocytopenia, neurologic symptoms, and renal abnormalities, but usually fever is involved, and the patient was afebrile. A catheter was placed for hemodialysis and therapeutic plasma exchange (TPE). Given that TTP-associated mortality is significantly decreased by use of TPE,¹⁵ this intervention was deemed prudent. The patient underwent TPE on three consecutive days, postop days 2 through 4.

The patient’s mental status began to improve, and by postop day 6, she was able to follow commands and engage in brief conversations. By postop day 9, she had returned almost completely to her baseline mental status.

The patient’s liver function test results and total bilirubin, ammonia, and creatinine levels all improved over the first few postoperative days but began to rise again by day 6. In response to worsening renal and hepatic functioning, the decision was made on postop day 9 to transfer the patient to a hospital with liver transplantation capabilities, should this procedure become necessary.

Discussion
AFLP is a rare condition specific to pregnancy, affecting 1/7,000 to 1/20,000 pregnancies. Due to the low incidence of this disease, randomized controlled trials to study it are not possible. Instead, clinicians must learn either from individual case studies or from retrospective syntheses of cases reported over time.^1,2,7 Fortunately, the wealth of information gleaned over the past 30 years has significantly reduced AFLP-associated maternal and fetal mortality and morbidity rates. In the 1980s, maternal and fetal mortality rates as high as 85% were reported.³ Worldwide, maternal mortality associated with AFLP has decreased significantly to 7% to 18%, whereas the fetal mortality rate has fallen to between 9% and 23%.^1,16,17

Common trends among women who have developed AFLP include nulliparity, multiparity, and advanced maternal age. One retrospective study of 57 women who had developed AFLP revealed that 35 cases (61%) involved first-time pregnancies. It also showed that 10 (18%) of the women had twins, and 14 (25%) were older than 35.² In another study of 35 cases of AFLP, 40% of the women were nulliparous, and 11.4% were multiparous, including one triplet gestation.¹² In a third, smaller study, 80% of women affected by AFLP were multiparous.¹⁰ Currently, there is no known evidence linking any maternal behavior to development of AFLP.

Presentation
Women who present with AFLP often experience vague, nonspecific symptoms, leading to misdiagnosis or delayed diagnosis. Objective measurements, including physical exam findings, laboratory studies, and other diagnostic tests, will help with a diagnosis. The most frequent initial symptoms are nausea and vomiting (in 70% of patients) and abdominal pain (50% to 80%), epigastric or right upper-quadrant.³ Other common symptoms include fatigue, malaise, anorexia, weight gain, polyuria, and polydipsia.^2,3,9,18,19

Because the presenting symptoms in AFLP can be vague, clinicians should complete a thorough physical exam to differentiate accurately among conditions associated with pregnancy. Physical signs present in women with AFLP can include jaundice, ascites, edema, confusion, abdominal tenderness, and fever. More severe cases can present with multisystem involvement, including acute renal failure, gastrointestinal bleeding, pancreatitis, coagulopathy, and hepatic encephalopathy.^3,4,9,18

Diagnostic Tests
Relevant laboratory tests include a complete blood count (CBC), liver studies, chemistry, coagulation studies, and urinalysis (see Table 1). Viral causes should be ruled out by way of a hepatitis panel.³ In AFLP, the CBC may show elevated white blood cells, decreased hemoglobin and hematocrit, and decreased platelets. Liver studies show elevated hepatic aminotransferase, bilirubin, LDH, and ammonia levels. Chemistry results show elevated blood urea nitrogen and creatinine, and decreased blood glucose. Coagulation factors are affected, and prolonged PTT, decreased fibrinogen, and proteinurea may also be found.⁹

Though invasive and not often necessary^4,13 (and not possible for the case patient), the definitive diagnostic test for AFLP is liver biopsy.^13,14 Biopsy reveals a microvesicular fatty infiltration of the hepatocytes as minute fat droplets surrounding a centrally located nucleus. These fatty infiltrates stain with oil red O, specific for fat. Inflammation is present in 50% of cases. There may also be a picture similar to cholestasis with bile thrombi or deposits within the hepatocytes.²⁰

Due to the risk for hemorrhage and the critical status of women with AFLP, biopsy is often not possible. Ultrasonography may show increased echogenicity; CT may show decreased or diffuse attenuation in the liver. These imaging studies, though possibly helpful in severe cases, often yield false-negative results.^3,20

In the absence of another explanation for the patient’s symptoms, the Swansea criteria are used for diagnosis of AFLP.¹ Six or more of the following criteria must be present to confirm this diagnosis: vomiting, abdominal pain, polydipsia or polyuria, encephalopathy, leukocytosis, elevated bilirubin, elevated liver enzymes, elevated ammonia, hypoglycemia, renal dysfunction, coagulopathy, elevated uric acid, ascites on ultrasound, and microvesicular steatosis on liver biopsy.^1,2,5

Pathophysiology
Normal functions of the liver include metabolism, protein synthesis, and manufacturing of blood coagulation proteins. These functions are disturbed in the presence of AFLP. Thus, women with this disease experience signs and symptoms related directly to the dysfunction of these processes.^20-22

Disturbances in the hepatocytes due to excess fatty acids impair the liver’s ability to convert unconjugated bilirubin into conjugated bilirubin, causing plasma levels of unconjugated bilirubin to rise. This increase in bilirubin explains the jaundiced appearance of women with AFLP. AFLP is often thought to occur in conjunction with preeclampsia in many, but not all, patients. Thrombocytopenia in these patients is felt to be secondary to peripheral vascular consumption. Conjugated bilirubin levels may also be increased due to decreased flow of conjugated bilirubin into the common bile duct.²¹

Another liver function that is disrupted is that of glycogen storage and conversion to glucose, and the liver’s ability to convert nutrients into glycogen is also impaired. Decreased storage of glycogen, along with the liver’s inability to break down previously stored glycogen, causes a decrease in serum glucose levels. Women with AFLP often require treatment with IV dextrose in response to marked hypoglycemia.^16,21,23

The liver dysfunction associated with AFLP reduces adequate production of clotting factors and coagulation proteins. Thrombocytopenia, elevated clotting times, and bleeding are all problems seen in AFLP. Mild to moderate elevations in serum aminotransferases and elevated LDH also occur in patients with AFLP.^23,24

Genetic Factor
There is little known about the etiology of AFLP, although recent data point to a genetic component that was found in as many as 62% of mothers in one study and in 25% of infants in another study.^20-22 Fatty acid oxidation (FAO) is one of the processes of hepatic mitochondria, a process that relies on several enzymes. When FAO is interrupted, fatty acids are deposited in the liver cells, as seen in histologic studies of AFLP.^25,26 The common thread in women with this disease is a mutation in one of the enzymes needed for FAO. This enzyme is the long-chain 3-hydroxyacyl-CoA dehydrogenase. Deficiencies in this enzyme are common in mothers with AFLP and their infants.^{3,16,20,23,27}

Differential Diagnosis
Several complications of pregnancy that involve the liver may, on presentation, mimic AFLP.^{16,20,23,24,28} The most common are hyperemesis gravidarum and intrahepatic cholestasis of pregnancy²³ (see Table 2^{16,20,23,24,28}); others are preeclampsia/eclampsia and HELLP syndrome. It is important to distinguish between the signs and symptoms associated with each of these disorders in order to provide the most effective treatment. Hepatitis serologies are important in the differential diagnosis when liver enzyme levels are exceptionally high.^4,16,22,28

Treatment
The most effective treatment for AFLP is delivery of the infant; often, this alone causes the signs and symptoms of AFLP to resolve.^8,21,27,29 In two of three cases in a small study by Aso et al,⁸ early delivery of the fetus led to complete resolution of symptoms and return to normal liver function. One of these patients was sent home four days after delivery; the other, 14 days later. Other patients may require more invasive treatment and support.⁸

Management in the ICU is often required to provide appropriate supportive care to the mother after delivery. Acute respiratory distress syndrome, pancreatitis, hemorrhage, encephalopathy, renal failure, and continual liver failure are among the severe complications associated with AFLP.^4,8,10 Many women require intubation, dialysis, fluid resuscitation, blood product transfusion, and vasopressor therapy.^3,8,11 Prophylactic antibiotics, IV steroids, and glucose may all be required in the supportive care and recovery of a mother with AFLP.^3,8,11

TPE has also been useful in instances of severe complications.1,3,6 In one retrospective study, Martin et al¹ recommended administration of TPE in patients with AFLP under the following circumstances:

(1) Deteriorating central nervous system abnormalities, such as sensorium changes or coma;

(2) Persistent coagulopathy requiring continued and aggressive blood product support with plasma, red cells, and/or cryoprecipitate;

(3) Advanced renal dysfunction that compromised fluid management;

(4) Progressive cardiopulmonary compromise; and/or

(5) Ongoing fluid management concerns, including significant ascites, edema, anuria/oliguria, and/or fluid overload.¹

In rare cases, liver transplantation is needed in patients with AFLP. Westbrook et al¹⁸ reviewed 54 cases of liver disease in pregnancy in one UK hospital between 1997 and 2008. Of these, six patients with encephalopathy or elevated lactate were listed for liver transplant, including just one with a diagnosis of AFLP. This woman never actually underwent transplant but recovered in response to medical management alone.¹⁸ According to data reported in June 2011 by the Organ Procurement and Transplantation Network,³⁰ liver transplantation was needed in only three US patients with AFLP between 2000 and 2011. Further retrospective studies on outcomes from transplant versus medical management should be considered to guide future decision making involving this invasive therapy.

The Case Patient
This 39-year-old patient presented during a routine prenatal visit with proteinuria and hypertension, possibly indicative of preeclampsia. Because of the serious nature of this potential diagnosis in pregnancy, she was admitted for monitoring and further testing. Although the diagnosis of AFLP was not confirmed until later, the patient’s preliminary lab studies showed elevated liver enzymes and low platelet counts, signifying the need for prompt intervention and delivery of the infant. At this point, the patient met criteria for HELLP syndrome, but AFLP was suspected after the initial finding of profound hypoglycemia led to further testing.

As an older mother experiencing pregnancy for the first time, this patient fit the profile for AFLP. She initially responded well after delivery of her infant but continued to experience complications. On the days that the patient was treated with TPE, her total bilirubin and liver enzymes were at their lowest. Perhaps this treatment should be considered in more cases of AFLP.

The patient was transferred to a hospital with liver transplantation capabilities, but she ultimately recovered without undergoing transplant.

Conclusion
For the primary obstetric care provider, being aware of the possible complications associated with pregnancy is important. Though uncommon, AFLP is a serious complication that should be ruled out in women who present with vague symptoms such as nausea, vomiting, and abdominal pain in the third trimester of pregnancy. The reduction in AFLP-associated morbidity and mortality during the past 20 years is a direct result of increased early recognition and therapeutic delivery.

Referral to a maternal fetal medicine specialist, gastroenterologist, hematologist, and/or nephrologist may be necessary and appropriate in the management of a woman with AFLP. Further study is indicated for use of TPE in more severe cases of AFLP, particularly in women affected by persistent thrombocytopenia and anemia.

The author would like to thank C. Leanne Browning, MD, obstetrics/gynecology, for her invaluable guidance and advice on this project.

References
1. Martin JN Jr, Briery CM, Rose CH, et al. Postpartum plasma exchange as adjunctive therapy for severe acute fatty liver of pregnancy. J Clin Apher. 2009;23(4):138-143.

2. Knight M, Nelson-Piercy C, Kurinczuk JJ; UK Obstetric Surveillance System. A prospective national study of acute fatty liver of pregnancy in the UK. Gut. 2008;57(7):951-956.

3. Barsoom MJ, Tierney BJ. Acute fatty liver of pregnancy (2011). http://emedicine.medscape.com/article/1562425-overview. Accessed January 21, 2013.

4. Ko HH, Yoshida E. Acute fatty liver of pregnancy. Can J Gastroenterol. 2006;20(1):25-30.

5. Rathi U, Bapat M, Rathi P, Abraham P. Effect of liver disease on maternal and fetal outcome: a prospective study. Indian J Gastroenterol. 2007;26(2):59-63.

6. Myers L. Postpartum plasma exchange in a woman with suspected thrombotic thrombocytopenic purpura (TTP) vs hemolysis, elevated liver enzymes, and low platelet syndrome (HELLP): a case study. Nephrol Nurs J. 2010;37(4):399-402.

7. Vigil-de Gracia P. Acute fatty liver and HELLP syndrome: two distinct pregnancy disorders. Int J Gynaecol Obstet. 2001;73(3):215-220.

8. Aso K, Hojo S, Yumoto Y, et al. Three cases of acute fatty liver of pregnancy: postpartum clinical course depends on interval between onset of symptoms and termination of pregnancy. J Matern Fetal Neonatal Med. 2010;23(9):1047-1049.

9. Wei Q, Zhang L, Liu X. Clinical diagnosis and treatment of acute fatty liver of pregnancy: a literature review and 11 new cases. J Obstet Gynaecol Res. 2010;36(4):751-756.

10. Barber MA, Eguiluz I, Martin A, et al. Acute fatty liver of pregnancy: analysis of five consecutive cases from a tertiary centre. J Obstet Gynaecol. 2010;30(3):241-243.

11. Ajayi AO, Alao MO. Case report: acute fatty liver of pregnancy in a 30-year-old Nigerian primigravida. Niger J Clin Pract. 2008;11(4):389-391.

12. Vigíl-de Gracia P, Montufar-Rueda C. Acute fatty liver of pregnancy: diagnosis, treatment, and outcome based on 35 consecutive cases. J Matern Fetal Neonatal Med. 2011;24(9):1143-1146.

13. Dey M, Reema K. Acute fatty liver of pregnancy. N Am J Med Sci. 2012;4(11):611-612.

14. Castro MA, Goodwin TM, Shaw KJ, et al. Disseminated intravascular coagulation and antithrombin III depression in acute fatty liver of pregnancy. Am J Obstet Gynecol. 1996;174(1 pt 1):211-216.

15. Altuntas F, Aydogdu I, Kabukcu S, et al. Therapeutic plasma exchange for the treatment of thrombotic thrombocytopenic purpura: a retrospective multicenter study. Transfus Apher Sci. 2007;36(1):57-67.

16. Hay JE. Liver disease in pregnancy. Hepatology. 2008;47(3):1067-1076.

17. Wand S, Waeschle RM, Von Ahsen N, et al. Acute fatty liver failure due to acute fatty liver of pregnancy. Minerva Anesthesiol. 2012;78(4):503-506.

18. Westbrook RH, Yeoman AD, Joshi D, et al. Outcomes of severe pregnancy-related liver disease: refining the role of transplantation. Am J Transplant. 2010;10(11):2520-2526.

19. Fesenmeier MF, Coppage KH, Lambers DS, et al. Acute fatty liver of pregnancy in 3 tertiary care centers. Am J Obstet Gynecol. 2005;192(5):1416-1419.

20. Bacq Y. Liver diseases unique to pregnancy: a 2010 update. Clin Res Hepatol Gastroenterol. 2011;35(3):182-193.

21. Huether SE. Alterations of digestive function. In: McCance KL, Huether SE, eds. Pathophysiology: The Biologic Basis for Disease in Adults and Children. 6th ed. St. Louis, MO: Mosby; 2009:1452-1515.

22. Huether SE. Structure and function of the digestive system. In: McCance KL, Huether SE, eds. Pathophysiology: The Biologic Basis for Disease in Adults and Children. 6th ed. St. Louis, MO: Mosby; 2009:1420-1451.

23. Schutt VA, Minuk GY. Liver diseases unique to pregnancy. Best Pract Res Clin Gastroenterol. 2007;21(5):771-792.

24. Pan C, Perumalswami PV. Pregnancy-related liver diseases. Clin Liver Dis. 2011;15(1):199-208.

25. Ibdah JA. Acute fatty liver of pregnancy: an update on pathogenesis and clinical implications. World J Gastroenterol. 2006;12(46):7397-7404.

26. Browning MF, Levy HL, Wilkins-Haug LE, et al. Fetal fatty acid oxidation defects and maternal liver disease in pregnancy. Obstet Gynecol. 2006;107(1):115-120.

27. Dekker RR, Schutte JM, Stekelenburg J, et al. Maternal mortality and severe maternal morbidity from acute fatty liver of pregnancy in the Netherlands. Eur J Obstet Gynecol Reprod Biol. 2011;157(1):27-31.

28. Lee NM, Brady CW. Liver disease in pregnancy. World J Gastroenterol. 2009;15(8):897-906.

29. Vora KS, Shah VR, Parikh GP. Acute fatty liver of pregnancy: a case report of an uncommon disease. Indian J Crit Care Med. 2009;13(1):34-36.

30. Organ Procurement and Transplantation Network, Scientific Registry of Transplant Recipients. OPTN/SRTR 2011 Annual Data Report: Liver. http://srtr.transplant.hrsa.gov/annual_reports/2011/pdf/03_%20liver_12.pdf. Accessed January 18, 2013.

The authors report no financial relationships relevant to this article.

CASE: Recurrent UTI and antibiotic resistance

A 53-year-old postmenopausal woman with a history of culture-proven recurrent Escherichia coli urinary tract infections (UTIs) presents to the clinic with symptoms of UTI. She was previously treated with a postcoital regimen of trimethoprim/sulfamethoxazole, based on sensitivities identified by culture. A past work-up of her upper and lower urinary tract was negative. You send a catheterized specimen for culture; again, E. coli is identified as the pathogen but proves resistant to her current antibiotic regimen.

What treatment alternatives, aside from antibiotics, are available for this patient—and how might they affect resistance?

Increased antibiotic usage has led to greater bacterial resistance, which is perpetuated by clonal spread. Resistant strains of E. coli have been found in household members, suggesting host-host transmission as a mechanism for dissemination. Alternative treatments that reduce the use of antibiotics may minimize bacterial resistance and increase the efficacy of treatment. In the TABLE , we summarize alternative approaches to the treatment of recurrent UTI. We also describe a strategy to alleviate symptoms.

Alternatives to antibiotics in the treatment and prevention of recurrent UTI

Vaginal estrogen is the only proven alternative to antibiotics for postmenopausal women

A lack of estrogen is a risk factor for UTI and is associated with atrophic mucosa, leading to decreased colonization with lactobacilli, increased vaginal pH, and E. coli colonization.

A randomized, double-blind, placebo-controlled trial of intravaginal estriol cream versus placebo in 93 postmenopausal women found a significant decrease in the rate of UTI among women who used the cream.¹ After 8 months of follow-up, the incidence of UTI was 0.5 vs 5.9 episodes per patient-year (P <.001). Interestingly, all pretreatment cultures were negative for lactobacilli. One month after treatment, 61% of women in the estriol group were culture-positive for lactobacilli, compared with 0% of the placebo group.¹

A 2008 Cochrane review of nine studies concluded that vaginal estrogen reduces the number of UTIs in postmenopausal women, with variation based on the type of estrogen and duration of use.²

Adverse effects are mild

Twenty-eight percent of the estriol group in the randomized trial described above withdrew from treatment, with 20% citing local side effects, including vaginal irritation, burning, or itching—all of which were mild and self-limited.¹ Other possible adverse effects include breast tenderness, vaginal bleeding or spotting, and discharge.²

Clinical recommendations

Given the efficacy of this therapy, we recommend topical estrogen for postmenopausal patients with recurrent UTIs.

Cranberry juice may reduce UTI, but many patients withdraw
from treatment

Cranberries belong to the Vaccinium species, which contains all flavonoids, including anthocyanins and proanthocyanidins. It was previously thought that the acidification of urine produced an antibacterial effect, but several trials have documented no change in urine levels of hippuric acid when cranberry products are given, with no acidification of the urine.³ Current theory suggests that cranberries prevent bacteria from adhering to the uroepithelial cells of the walls of the bladder, by blocking expression of E. coli’s adhesion molecule, P. fimbriae, so that bacteria are unable to penetrate the mucosal surface.^4,5 The major benefit of cranberry products over antibiotic prophylaxis is that they do not have the potential for resistance.⁴

A 2008 Cochrane review concluded that cranberry juice may reduce symptomatic UTIs, particularly among young, sexually active women—but there is a high rate of withdrawal from treatment.⁶ The optimal method of administration and dose remain unclear. In contrast, two recent randomized, controlled trials—published after the Cochrane review—found no difference in the rate of recurrent UTI in premenopausal women.^7,8 Adverse effects in these two trials included constipation, heartburn, loose stools, vaginal itching and dryness, and migraines. Of note, there was no statistical difference in side effects between the cranberry and placebo groups.⁷

Vaccinium tablets may be protective in older women

Cranberry extracts of 500 mg to 1,000 mg daily have been compared with antimicrobial prophylaxis in two randomized, double-blind, controlled trials. The trials demonstrated mixed benefits. Trimethoprim/sulfamethoxazole was associated with a lower rate of UTI in younger women, compared with cranberry extracts alone (P=.02), while cranberry extracts were slightly more effective than trimethoprim alone in older women.^9,10 Cranberry tablets were not associated with bacterial resistance, were cheaper, and were viewed as a more natural option. The interventions were equally well tolerated.

Overall efficacy of cranberry tablets is unclear. Side effects, albeit mild, included gastrointestinal disturbances, vaginal complaints, and rash or urticaria. There was no significant difference in the rate of adverse effects between antimicrobial treatment and cranberry tablets.⁹

Cystopurin has not been studied

Cystopurin is an over-the-counter (OTC) tablet containing cranberry extract and potassium citrate that is taken three times daily (3 g/dose) for 2 days. Interestingly, although a proposed mechanism for the efficacy of vitamin C and cranberry juice has been a reduction of pH, potassium citrate is an alkalizing agent that is reported to relieve burning and reduce urinary urgency and frequency. No studies have assessed this medication in the treatment of a UTI or its symptoms.

Clinical recommendations

The evidence is mixed on the use of cranberry products to reduce recurrent UTI. However, given the limited side effects associated with these products, we offer cranberry tablets to patients who have recurrent UTIs who are interested in a more natural alternative.

We generally do not recommend cranberry juice because the added fluid volume tends to exacerbate frequency and urgency symptoms.

Lactobacilli suppositories may benefit
postmenopausal women

Lactobacilli are fastidious gram-positive rods and are usually the dominant component of the vaginal flora.¹¹ They prevent colonization and infection by more virulent bacteria by competing for adhesion receptors and nutrients as well as producing antimicrobial substances such as hydrogen peroxide and lactic acid. A decrease in lactobacilli leaves the urinary tract susceptible to infectious organisms that may colonize the vaginal mucosa and increase the risk of recurrent UTI.^12-14

A 2008 review of randomized, controlled trials of oral lactobacilli and UTI was inconclusive, due to inconsistent dosing strategies and small sample sizes.¹⁵ A 2011 randomized, double-blind, placebo-controlled phase 2 trial of Lactin-V, a lactobacilli vaginal suppository, found that it reduced the rate of recurrent UTI. Lactin-V contains a hydrogen-peroxide–producing Lactobacillus crispatus developed as a probiotic that was determined to be safe and tolerable as a vaginal suppository in a phase 1 trial.¹⁶ The phase 2 trial enrolled 100 young premenopausal women with a history of recurrent UTI who took either Lactin-V or placebo daily for 5 days, then weekly for 10 weeks. Women in the Lactin-V group who had high levels of L. crispatus colonization experienced a significant reduction in the rate of UTI (15% vs 27% in the placebo group), but the effect did not reach statistical significance.¹⁴

Little difference in adverse effects

Adverse effects were reported among 56% of patients who received Lactin-V versus 50% of those given placebo. The most common of these were vaginal discharge, itching, and moderate abdominal discomfort.¹⁴ Although lactobacillus can potentially promote UTI, this phenomenon is rare.¹¹

Regrettably, Lactin-V is not currently available in the United States. However, there are other lactobacilli vaginal suppositories on the market ( TABLE ). Given the low risk associated with their use, they should be considered as an alternative for patients who cannot or will not use estrogen.

Clinical recommendations

Probiotics such as lactobacilli are categorized as “dietary supplements”; as such, they are not regulated by the US Food and Drug Administration. We recommend the use of lactobacilli suppositories in postmenopausal women who have a contraindication to (or prefer to avoid) vaginal estrogen.

Skip blueberry products for now

Like cranberries, blueberries belong to the Vaccinium species and are thought to interfere with bacterial adhesion to the walls of the bladder. One in vitro trial suggests that blueberries also have antiproliferation effects, although no clinical studies have been performed to date to further investigate safety or efficacy.⁴ Consequently, we do not recommend use of these products.

Methenamine salts may benefit some populations

These anti-infective agents, including methenamine hippurate and methenamine mandelate, often are used to prevent UTI. They are found in combination OTC medications, such as Prosed DS and Urelle. Methenamine salts are bacteriostatic to all urinary tract pathogens due to their production of formaldehyde.^3,16

Although methenamine produces varying concentrations of formaldehyde, depending on the acidity of the urine, there is no evidence that acidified urine enhances methenamine’s effects.¹⁶

Advantages of methenamine include the fact that it produces no changes in gut flora, poses no risk for antimicrobial resistance, and has low toxicity. It also is low in cost.¹⁷

Methenamine is contraindicated in patients with renal insufficiency or severe hepatic disease.

Adverse reactions are generally mild and include gastrointestinal disturbances, skin rashes, dysuria, and microscopic hematuria.¹⁶

Methenamine hippurate

A 2007 Cochrane review, deemed up to date in 2010, analyzed 13 randomized, controlled trials involving 2,032 participants. Subgroup analyses suggested that methenamine hippurate may be of some benefit to patients without renal tract abnormalities; these patients experienced significantly reduced symptoms after short-term treatment of 1 week or less.

Patients with spinal injury do not appear to benefit from treatment, according to a randomized, double-blind, placebo-controlled trial by Lee and colleagues.¹⁸

Methenamine mandelate

This agent is commonly used to prevent recurrent UTI, although there is a paucity of randomized, controlled trials to support its use. One such trial in patients with neurogenic bladder found that methenamine mandelate with acidification was superior to placebo (P <.02) for preventing UTI.¹⁹ Beyond this population, however, it’s difficult to assess methenamine’s efficacy in the prevention of recurrent UTI.

Methylene blue may be useful in the elderly

Methylene blue is a light-activated compound described as “photodynamic antimicrobial chemotherapy” (PACT). Once illuminated, it becomes a bactericide, causing excitation of electrons followed by one of two reactions:

• reduction oxidation
• formation of a labile singlet oxygen and then oxidation.

This makes resistance unlikely.

In an in vitro study, methylene blue was as effective as levofloxacin against Pseudomonas aeruginosa, Klebsiella pneumonia, Proteus mirabilis, Enterococcus, and Staphylococcus aureus when illuminated.

Potential benefits of this mode of treatment include local exposure and no drug interactions.

We suggest that methylene blue be placed and illuminated with a special catheter that would target UTI in the elderly population, among whom 52% of UTIs are associated with use of catheters.²⁰ In vivo effects, adverse effects, and cost are not known, which limits current applicability of this compound.

Vitamin C may reduce UTI in pregnancy

The proposed mechanism for the efficacy of vitamin C for the treatment of UTI is the acidification of urine, which is believed to reduce the proliferation of bacteria. However, several studies have shown that vitamin C, at various doses, does not reliably reduce urine pH.^15,21,22 Nonetheless, ascorbic acid was tested for its effect on UTI prevention during pregnancy.

In a single-blind trial, 110 pregnant women were divided into two groups (55 in each group):

• One group received ferrous sulfate (200 mg), folic acid (5 mg), and vitamin C (100 mg) daily for 3 months
• The other received ferrous sulfate (200 mg) and folic acid (5 mg) daily for 3 months.

Urine was cultured monthly. The incidence of UTI was significantly lower in the group receiving vitamin C (12.7%), compared with the control group (29.1%) (P=.03; odds ratio [OR], 0.35).²³

Uva ursi may have a prophylactic effect

Uva ursi (UVA-E) is one of the most commonly used herbal supplements for treatment of UTI. The crude extract from Bearberry or Arctostaphylos uva-ursi has been shown to act as an antimicrobial by decreasing bacterial adherence.²⁴ In addition, investigators have found the extract to have diuretic and anti-inflammatory properties.^25,26 However, few studies have explored its efficacy. One randomized, controlled trial that included 57 women (30 allocated to UVA-E and 27 to placebo) found a statistically significant reduction in the rate of recurrence at 1 year among women taking UVA-E, compared with those who did not.²⁷

Note that the women in this trial were given UVA-E for 1 month only. Long-term use of this herb has not been studied and may cause liver damage.

In a mouse model, forskolin reduced urinary-tract E. coli

This herb is derived from Indian coleus (Coleus forskohlii), a member of the mint family. It has been used primarily for its antiasthmatic, spasmolytic, and antihypertensive effects. It is believed to activate adenylate cyclase, increasing intracellular cyclic AMP (cAMP) concentrations and activating a number of key enzymatic pathways.²⁸

The findings of a recent observational study have spurred the use of forskolin in the treatment of recurrent UTI.²⁹ In the study, conducted on mice, when forskolin was injected into the bladder, intracellular E. coli decreased.

It is theorized that the incorporation of bacteria into intracellular vesicles of the bladder prevents exposure to antibiotics. When combined with an antibiotic, forskolin may increase bacterial elimination and thus lower the risk of recurrent infection. However, no randomized trials have evaluated the efficacy of this treatment.

Patients who are already taking antihypertensive medications should be cautious when using this herb, as it may lead to a drop in blood pressure.

Behavior changes are risk-free

One of the natural mechanisms that promotes bacterial elimination and prevents bacterial growth is urination. A recent review article on the subject found several contradictory studies on the effect of fluid intake on the risk of UTI.³⁰ Although there is no definitive evidence that susceptibility to UTI is linked to fluid intake, adequate hydration may reduce the risk of recurrent infection.

Similarly, voiding shortly after sexual intercourse may prevent UTI. One case-control study found a modest protective effect in patients who voided after intercourse.³¹

Clinical recommendations

Given the low risk of these measures, it seems reasonable to recommend postcoital voiding and increased fluid intake to prevent recurrent UTI.

A focus on symptoms

Phenazopyridine, the chemical found in numerous OTC medications, such as Pyridium, AZO, and Uristat, was discovered by Swiss chemist Bernhard Joos in the 1950s. Its mechanism of action is still unclear, but approximately 65% of the oral dose is excreted by the kidneys, where it has a direct topical analgesic effect.^32,33

Clinical recommendations

Patients should be warned that phenazopyridine will lead to orange urine discoloration.

The medication is generally well tolerated but should be used with caution in patients with acute renal failure, hemolytic anemia, or methemoglobinemia, as it may exacerbate these conditions.

Last words

Recurrent UTIs are common and impose a significant financial burden on our healthcare system. Although there are several antibiotic treatment options and dosing regimens available, increasing antibiotic resistance has made management of recurrent UTIs more difficult. Effective alternative treatments that reduce the reliance on antibiotics may minimize bacterial resistance and decrease the financial burden of this common condition.

CASE: Resolved

To reduce vaginal E. coli, the patient is started on vaginal estrogen cream. She is also advised to purchase cranberry tablets to help prevent future infections. Last, she is counseled about behavioral changes she can make and prescribed a short course of antibiotics to treat her culture-proven infection.

We want to hear from you!  Tell us what you think.

The authors report no financial relationships relevant to this article.

CASE: Recurrent UTI and antibiotic resistance

A 53-year-old postmenopausal woman with a history of culture-proven recurrent Escherichia coli urinary tract infections (UTIs) presents to the clinic with symptoms of UTI. She was previously treated with a postcoital regimen of trimethoprim/sulfamethoxazole, based on sensitivities identified by culture. A past work-up of her upper and lower urinary tract was negative. You send a catheterized specimen for culture; again, E. coli is identified as the pathogen but proves resistant to her current antibiotic regimen.

What treatment alternatives, aside from antibiotics, are available for this patient—and how might they affect resistance?

Increased antibiotic usage has led to greater bacterial resistance, which is perpetuated by clonal spread. Resistant strains of E. coli have been found in household members, suggesting host-host transmission as a mechanism for dissemination. Alternative treatments that reduce the use of antibiotics may minimize bacterial resistance and increase the efficacy of treatment. In the TABLE , we summarize alternative approaches to the treatment of recurrent UTI. We also describe a strategy to alleviate symptoms.

Alternatives to antibiotics in the treatment and prevention of recurrent UTI

Vaginal estrogen is the only proven alternative to antibiotics for postmenopausal women

A lack of estrogen is a risk factor for UTI and is associated with atrophic mucosa, leading to decreased colonization with lactobacilli, increased vaginal pH, and E. coli colonization.

A randomized, double-blind, placebo-controlled trial of intravaginal estriol cream versus placebo in 93 postmenopausal women found a significant decrease in the rate of UTI among women who used the cream.¹ After 8 months of follow-up, the incidence of UTI was 0.5 vs 5.9 episodes per patient-year (P <.001). Interestingly, all pretreatment cultures were negative for lactobacilli. One month after treatment, 61% of women in the estriol group were culture-positive for lactobacilli, compared with 0% of the placebo group.¹

A 2008 Cochrane review of nine studies concluded that vaginal estrogen reduces the number of UTIs in postmenopausal women, with variation based on the type of estrogen and duration of use.²

Adverse effects are mild

Twenty-eight percent of the estriol group in the randomized trial described above withdrew from treatment, with 20% citing local side effects, including vaginal irritation, burning, or itching—all of which were mild and self-limited.¹ Other possible adverse effects include breast tenderness, vaginal bleeding or spotting, and discharge.²

Clinical recommendations

Given the efficacy of this therapy, we recommend topical estrogen for postmenopausal patients with recurrent UTIs.

Cranberry juice may reduce UTI, but many patients withdraw
from treatment

Cranberries belong to the Vaccinium species, which contains all flavonoids, including anthocyanins and proanthocyanidins. It was previously thought that the acidification of urine produced an antibacterial effect, but several trials have documented no change in urine levels of hippuric acid when cranberry products are given, with no acidification of the urine.³ Current theory suggests that cranberries prevent bacteria from adhering to the uroepithelial cells of the walls of the bladder, by blocking expression of E. coli’s adhesion molecule, P. fimbriae, so that bacteria are unable to penetrate the mucosal surface.^4,5 The major benefit of cranberry products over antibiotic prophylaxis is that they do not have the potential for resistance.⁴

A 2008 Cochrane review concluded that cranberry juice may reduce symptomatic UTIs, particularly among young, sexually active women—but there is a high rate of withdrawal from treatment.⁶ The optimal method of administration and dose remain unclear. In contrast, two recent randomized, controlled trials—published after the Cochrane review—found no difference in the rate of recurrent UTI in premenopausal women.^7,8 Adverse effects in these two trials included constipation, heartburn, loose stools, vaginal itching and dryness, and migraines. Of note, there was no statistical difference in side effects between the cranberry and placebo groups.⁷

Vaccinium tablets may be protective in older women

Cranberry extracts of 500 mg to 1,000 mg daily have been compared with antimicrobial prophylaxis in two randomized, double-blind, controlled trials. The trials demonstrated mixed benefits. Trimethoprim/sulfamethoxazole was associated with a lower rate of UTI in younger women, compared with cranberry extracts alone (P=.02), while cranberry extracts were slightly more effective than trimethoprim alone in older women.^9,10 Cranberry tablets were not associated with bacterial resistance, were cheaper, and were viewed as a more natural option. The interventions were equally well tolerated.

Overall efficacy of cranberry tablets is unclear. Side effects, albeit mild, included gastrointestinal disturbances, vaginal complaints, and rash or urticaria. There was no significant difference in the rate of adverse effects between antimicrobial treatment and cranberry tablets.⁹

Cystopurin has not been studied

Cystopurin is an over-the-counter (OTC) tablet containing cranberry extract and potassium citrate that is taken three times daily (3 g/dose) for 2 days. Interestingly, although a proposed mechanism for the efficacy of vitamin C and cranberry juice has been a reduction of pH, potassium citrate is an alkalizing agent that is reported to relieve burning and reduce urinary urgency and frequency. No studies have assessed this medication in the treatment of a UTI or its symptoms.

Clinical recommendations

The evidence is mixed on the use of cranberry products to reduce recurrent UTI. However, given the limited side effects associated with these products, we offer cranberry tablets to patients who have recurrent UTIs who are interested in a more natural alternative.

We generally do not recommend cranberry juice because the added fluid volume tends to exacerbate frequency and urgency symptoms.

Lactobacilli suppositories may benefit
postmenopausal women

Lactobacilli are fastidious gram-positive rods and are usually the dominant component of the vaginal flora.¹¹ They prevent colonization and infection by more virulent bacteria by competing for adhesion receptors and nutrients as well as producing antimicrobial substances such as hydrogen peroxide and lactic acid. A decrease in lactobacilli leaves the urinary tract susceptible to infectious organisms that may colonize the vaginal mucosa and increase the risk of recurrent UTI.^12-14

A 2008 review of randomized, controlled trials of oral lactobacilli and UTI was inconclusive, due to inconsistent dosing strategies and small sample sizes.¹⁵ A 2011 randomized, double-blind, placebo-controlled phase 2 trial of Lactin-V, a lactobacilli vaginal suppository, found that it reduced the rate of recurrent UTI. Lactin-V contains a hydrogen-peroxide–producing Lactobacillus crispatus developed as a probiotic that was determined to be safe and tolerable as a vaginal suppository in a phase 1 trial.¹⁶ The phase 2 trial enrolled 100 young premenopausal women with a history of recurrent UTI who took either Lactin-V or placebo daily for 5 days, then weekly for 10 weeks. Women in the Lactin-V group who had high levels of L. crispatus colonization experienced a significant reduction in the rate of UTI (15% vs 27% in the placebo group), but the effect did not reach statistical significance.¹⁴

Little difference in adverse effects

Adverse effects were reported among 56% of patients who received Lactin-V versus 50% of those given placebo. The most common of these were vaginal discharge, itching, and moderate abdominal discomfort.¹⁴ Although lactobacillus can potentially promote UTI, this phenomenon is rare.¹¹

Regrettably, Lactin-V is not currently available in the United States. However, there are other lactobacilli vaginal suppositories on the market ( TABLE ). Given the low risk associated with their use, they should be considered as an alternative for patients who cannot or will not use estrogen.

Clinical recommendations

Probiotics such as lactobacilli are categorized as “dietary supplements”; as such, they are not regulated by the US Food and Drug Administration. We recommend the use of lactobacilli suppositories in postmenopausal women who have a contraindication to (or prefer to avoid) vaginal estrogen.

Skip blueberry products for now

Like cranberries, blueberries belong to the Vaccinium species and are thought to interfere with bacterial adhesion to the walls of the bladder. One in vitro trial suggests that blueberries also have antiproliferation effects, although no clinical studies have been performed to date to further investigate safety or efficacy.⁴ Consequently, we do not recommend use of these products.

Methenamine salts may benefit some populations

These anti-infective agents, including methenamine hippurate and methenamine mandelate, often are used to prevent UTI. They are found in combination OTC medications, such as Prosed DS and Urelle. Methenamine salts are bacteriostatic to all urinary tract pathogens due to their production of formaldehyde.^3,16

Although methenamine produces varying concentrations of formaldehyde, depending on the acidity of the urine, there is no evidence that acidified urine enhances methenamine’s effects.¹⁶

Advantages of methenamine include the fact that it produces no changes in gut flora, poses no risk for antimicrobial resistance, and has low toxicity. It also is low in cost.¹⁷

Methenamine is contraindicated in patients with renal insufficiency or severe hepatic disease.

Adverse reactions are generally mild and include gastrointestinal disturbances, skin rashes, dysuria, and microscopic hematuria.¹⁶

Methenamine hippurate

A 2007 Cochrane review, deemed up to date in 2010, analyzed 13 randomized, controlled trials involving 2,032 participants. Subgroup analyses suggested that methenamine hippurate may be of some benefit to patients without renal tract abnormalities; these patients experienced significantly reduced symptoms after short-term treatment of 1 week or less.

Patients with spinal injury do not appear to benefit from treatment, according to a randomized, double-blind, placebo-controlled trial by Lee and colleagues.¹⁸

Methenamine mandelate

This agent is commonly used to prevent recurrent UTI, although there is a paucity of randomized, controlled trials to support its use. One such trial in patients with neurogenic bladder found that methenamine mandelate with acidification was superior to placebo (P <.02) for preventing UTI.¹⁹ Beyond this population, however, it’s difficult to assess methenamine’s efficacy in the prevention of recurrent UTI.

Methylene blue may be useful in the elderly

Methylene blue is a light-activated compound described as “photodynamic antimicrobial chemotherapy” (PACT). Once illuminated, it becomes a bactericide, causing excitation of electrons followed by one of two reactions:

• reduction oxidation
• formation of a labile singlet oxygen and then oxidation.

This makes resistance unlikely.

In an in vitro study, methylene blue was as effective as levofloxacin against Pseudomonas aeruginosa, Klebsiella pneumonia, Proteus mirabilis, Enterococcus, and Staphylococcus aureus when illuminated.

Potential benefits of this mode of treatment include local exposure and no drug interactions.

We suggest that methylene blue be placed and illuminated with a special catheter that would target UTI in the elderly population, among whom 52% of UTIs are associated with use of catheters.²⁰ In vivo effects, adverse effects, and cost are not known, which limits current applicability of this compound.

Vitamin C may reduce UTI in pregnancy

The proposed mechanism for the efficacy of vitamin C for the treatment of UTI is the acidification of urine, which is believed to reduce the proliferation of bacteria. However, several studies have shown that vitamin C, at various doses, does not reliably reduce urine pH.^15,21,22 Nonetheless, ascorbic acid was tested for its effect on UTI prevention during pregnancy.

In a single-blind trial, 110 pregnant women were divided into two groups (55 in each group):

• One group received ferrous sulfate (200 mg), folic acid (5 mg), and vitamin C (100 mg) daily for 3 months
• The other received ferrous sulfate (200 mg) and folic acid (5 mg) daily for 3 months.

Urine was cultured monthly. The incidence of UTI was significantly lower in the group receiving vitamin C (12.7%), compared with the control group (29.1%) (P=.03; odds ratio [OR], 0.35).²³

Uva ursi may have a prophylactic effect

Uva ursi (UVA-E) is one of the most commonly used herbal supplements for treatment of UTI. The crude extract from Bearberry or Arctostaphylos uva-ursi has been shown to act as an antimicrobial by decreasing bacterial adherence.²⁴ In addition, investigators have found the extract to have diuretic and anti-inflammatory properties.^25,26 However, few studies have explored its efficacy. One randomized, controlled trial that included 57 women (30 allocated to UVA-E and 27 to placebo) found a statistically significant reduction in the rate of recurrence at 1 year among women taking UVA-E, compared with those who did not.²⁷

Note that the women in this trial were given UVA-E for 1 month only. Long-term use of this herb has not been studied and may cause liver damage.

In a mouse model, forskolin reduced urinary-tract E. coli

This herb is derived from Indian coleus (Coleus forskohlii), a member of the mint family. It has been used primarily for its antiasthmatic, spasmolytic, and antihypertensive effects. It is believed to activate adenylate cyclase, increasing intracellular cyclic AMP (cAMP) concentrations and activating a number of key enzymatic pathways.²⁸

The findings of a recent observational study have spurred the use of forskolin in the treatment of recurrent UTI.²⁹ In the study, conducted on mice, when forskolin was injected into the bladder, intracellular E. coli decreased.

It is theorized that the incorporation of bacteria into intracellular vesicles of the bladder prevents exposure to antibiotics. When combined with an antibiotic, forskolin may increase bacterial elimination and thus lower the risk of recurrent infection. However, no randomized trials have evaluated the efficacy of this treatment.

Patients who are already taking antihypertensive medications should be cautious when using this herb, as it may lead to a drop in blood pressure.

Behavior changes are risk-free

One of the natural mechanisms that promotes bacterial elimination and prevents bacterial growth is urination. A recent review article on the subject found several contradictory studies on the effect of fluid intake on the risk of UTI.³⁰ Although there is no definitive evidence that susceptibility to UTI is linked to fluid intake, adequate hydration may reduce the risk of recurrent infection.

Similarly, voiding shortly after sexual intercourse may prevent UTI. One case-control study found a modest protective effect in patients who voided after intercourse.³¹

Clinical recommendations

Given the low risk of these measures, it seems reasonable to recommend postcoital voiding and increased fluid intake to prevent recurrent UTI.

A focus on symptoms

Phenazopyridine, the chemical found in numerous OTC medications, such as Pyridium, AZO, and Uristat, was discovered by Swiss chemist Bernhard Joos in the 1950s. Its mechanism of action is still unclear, but approximately 65% of the oral dose is excreted by the kidneys, where it has a direct topical analgesic effect.^32,33

Clinical recommendations

Patients should be warned that phenazopyridine will lead to orange urine discoloration.

The medication is generally well tolerated but should be used with caution in patients with acute renal failure, hemolytic anemia, or methemoglobinemia, as it may exacerbate these conditions.

Last words

Recurrent UTIs are common and impose a significant financial burden on our healthcare system. Although there are several antibiotic treatment options and dosing regimens available, increasing antibiotic resistance has made management of recurrent UTIs more difficult. Effective alternative treatments that reduce the reliance on antibiotics may minimize bacterial resistance and decrease the financial burden of this common condition.

CASE: Resolved

To reduce vaginal E. coli, the patient is started on vaginal estrogen cream. She is also advised to purchase cranberry tablets to help prevent future infections. Last, she is counseled about behavioral changes she can make and prescribed a short course of antibiotics to treat her culture-proven infection.

We want to hear from you!  Tell us what you think.

The authors report no financial relationships relevant to this article.

CASE: Recurrent UTI and antibiotic resistance

A 53-year-old postmenopausal woman with a history of culture-proven recurrent Escherichia coli urinary tract infections (UTIs) presents to the clinic with symptoms of UTI. She was previously treated with a postcoital regimen of trimethoprim/sulfamethoxazole, based on sensitivities identified by culture. A past work-up of her upper and lower urinary tract was negative. You send a catheterized specimen for culture; again, E. coli is identified as the pathogen but proves resistant to her current antibiotic regimen.

What treatment alternatives, aside from antibiotics, are available for this patient—and how might they affect resistance?

Increased antibiotic usage has led to greater bacterial resistance, which is perpetuated by clonal spread. Resistant strains of E. coli have been found in household members, suggesting host-host transmission as a mechanism for dissemination. Alternative treatments that reduce the use of antibiotics may minimize bacterial resistance and increase the efficacy of treatment. In the TABLE , we summarize alternative approaches to the treatment of recurrent UTI. We also describe a strategy to alleviate symptoms.

Alternatives to antibiotics in the treatment and prevention of recurrent UTI

Vaginal estrogen is the only proven alternative to antibiotics for postmenopausal women

A lack of estrogen is a risk factor for UTI and is associated with atrophic mucosa, leading to decreased colonization with lactobacilli, increased vaginal pH, and E. coli colonization.

A randomized, double-blind, placebo-controlled trial of intravaginal estriol cream versus placebo in 93 postmenopausal women found a significant decrease in the rate of UTI among women who used the cream.¹ After 8 months of follow-up, the incidence of UTI was 0.5 vs 5.9 episodes per patient-year (P <.001). Interestingly, all pretreatment cultures were negative for lactobacilli. One month after treatment, 61% of women in the estriol group were culture-positive for lactobacilli, compared with 0% of the placebo group.¹

A 2008 Cochrane review of nine studies concluded that vaginal estrogen reduces the number of UTIs in postmenopausal women, with variation based on the type of estrogen and duration of use.²

Adverse effects are mild

Twenty-eight percent of the estriol group in the randomized trial described above withdrew from treatment, with 20% citing local side effects, including vaginal irritation, burning, or itching—all of which were mild and self-limited.¹ Other possible adverse effects include breast tenderness, vaginal bleeding or spotting, and discharge.²

Clinical recommendations

Given the efficacy of this therapy, we recommend topical estrogen for postmenopausal patients with recurrent UTIs.

Cranberry juice may reduce UTI, but many patients withdraw
from treatment

Cranberries belong to the Vaccinium species, which contains all flavonoids, including anthocyanins and proanthocyanidins. It was previously thought that the acidification of urine produced an antibacterial effect, but several trials have documented no change in urine levels of hippuric acid when cranberry products are given, with no acidification of the urine.³ Current theory suggests that cranberries prevent bacteria from adhering to the uroepithelial cells of the walls of the bladder, by blocking expression of E. coli’s adhesion molecule, P. fimbriae, so that bacteria are unable to penetrate the mucosal surface.^4,5 The major benefit of cranberry products over antibiotic prophylaxis is that they do not have the potential for resistance.⁴

A 2008 Cochrane review concluded that cranberry juice may reduce symptomatic UTIs, particularly among young, sexually active women—but there is a high rate of withdrawal from treatment.⁶ The optimal method of administration and dose remain unclear. In contrast, two recent randomized, controlled trials—published after the Cochrane review—found no difference in the rate of recurrent UTI in premenopausal women.^7,8 Adverse effects in these two trials included constipation, heartburn, loose stools, vaginal itching and dryness, and migraines. Of note, there was no statistical difference in side effects between the cranberry and placebo groups.⁷

Vaccinium tablets may be protective in older women

Cranberry extracts of 500 mg to 1,000 mg daily have been compared with antimicrobial prophylaxis in two randomized, double-blind, controlled trials. The trials demonstrated mixed benefits. Trimethoprim/sulfamethoxazole was associated with a lower rate of UTI in younger women, compared with cranberry extracts alone (P=.02), while cranberry extracts were slightly more effective than trimethoprim alone in older women.^9,10 Cranberry tablets were not associated with bacterial resistance, were cheaper, and were viewed as a more natural option. The interventions were equally well tolerated.

Overall efficacy of cranberry tablets is unclear. Side effects, albeit mild, included gastrointestinal disturbances, vaginal complaints, and rash or urticaria. There was no significant difference in the rate of adverse effects between antimicrobial treatment and cranberry tablets.⁹

Cystopurin has not been studied

Cystopurin is an over-the-counter (OTC) tablet containing cranberry extract and potassium citrate that is taken three times daily (3 g/dose) for 2 days. Interestingly, although a proposed mechanism for the efficacy of vitamin C and cranberry juice has been a reduction of pH, potassium citrate is an alkalizing agent that is reported to relieve burning and reduce urinary urgency and frequency. No studies have assessed this medication in the treatment of a UTI or its symptoms.

Clinical recommendations

The evidence is mixed on the use of cranberry products to reduce recurrent UTI. However, given the limited side effects associated with these products, we offer cranberry tablets to patients who have recurrent UTIs who are interested in a more natural alternative.

We generally do not recommend cranberry juice because the added fluid volume tends to exacerbate frequency and urgency symptoms.

Lactobacilli suppositories may benefit
postmenopausal women

Lactobacilli are fastidious gram-positive rods and are usually the dominant component of the vaginal flora.¹¹ They prevent colonization and infection by more virulent bacteria by competing for adhesion receptors and nutrients as well as producing antimicrobial substances such as hydrogen peroxide and lactic acid. A decrease in lactobacilli leaves the urinary tract susceptible to infectious organisms that may colonize the vaginal mucosa and increase the risk of recurrent UTI.^12-14

A 2008 review of randomized, controlled trials of oral lactobacilli and UTI was inconclusive, due to inconsistent dosing strategies and small sample sizes.¹⁵ A 2011 randomized, double-blind, placebo-controlled phase 2 trial of Lactin-V, a lactobacilli vaginal suppository, found that it reduced the rate of recurrent UTI. Lactin-V contains a hydrogen-peroxide–producing Lactobacillus crispatus developed as a probiotic that was determined to be safe and tolerable as a vaginal suppository in a phase 1 trial.¹⁶ The phase 2 trial enrolled 100 young premenopausal women with a history of recurrent UTI who took either Lactin-V or placebo daily for 5 days, then weekly for 10 weeks. Women in the Lactin-V group who had high levels of L. crispatus colonization experienced a significant reduction in the rate of UTI (15% vs 27% in the placebo group), but the effect did not reach statistical significance.¹⁴

Little difference in adverse effects

Adverse effects were reported among 56% of patients who received Lactin-V versus 50% of those given placebo. The most common of these were vaginal discharge, itching, and moderate abdominal discomfort.¹⁴ Although lactobacillus can potentially promote UTI, this phenomenon is rare.¹¹

Regrettably, Lactin-V is not currently available in the United States. However, there are other lactobacilli vaginal suppositories on the market ( TABLE ). Given the low risk associated with their use, they should be considered as an alternative for patients who cannot or will not use estrogen.

Clinical recommendations

Probiotics such as lactobacilli are categorized as “dietary supplements”; as such, they are not regulated by the US Food and Drug Administration. We recommend the use of lactobacilli suppositories in postmenopausal women who have a contraindication to (or prefer to avoid) vaginal estrogen.

Skip blueberry products for now

Like cranberries, blueberries belong to the Vaccinium species and are thought to interfere with bacterial adhesion to the walls of the bladder. One in vitro trial suggests that blueberries also have antiproliferation effects, although no clinical studies have been performed to date to further investigate safety or efficacy.⁴ Consequently, we do not recommend use of these products.

Methenamine salts may benefit some populations

These anti-infective agents, including methenamine hippurate and methenamine mandelate, often are used to prevent UTI. They are found in combination OTC medications, such as Prosed DS and Urelle. Methenamine salts are bacteriostatic to all urinary tract pathogens due to their production of formaldehyde.^3,16

Although methenamine produces varying concentrations of formaldehyde, depending on the acidity of the urine, there is no evidence that acidified urine enhances methenamine’s effects.¹⁶

Advantages of methenamine include the fact that it produces no changes in gut flora, poses no risk for antimicrobial resistance, and has low toxicity. It also is low in cost.¹⁷

Methenamine is contraindicated in patients with renal insufficiency or severe hepatic disease.

Adverse reactions are generally mild and include gastrointestinal disturbances, skin rashes, dysuria, and microscopic hematuria.¹⁶

Methenamine hippurate

A 2007 Cochrane review, deemed up to date in 2010, analyzed 13 randomized, controlled trials involving 2,032 participants. Subgroup analyses suggested that methenamine hippurate may be of some benefit to patients without renal tract abnormalities; these patients experienced significantly reduced symptoms after short-term treatment of 1 week or less.

Patients with spinal injury do not appear to benefit from treatment, according to a randomized, double-blind, placebo-controlled trial by Lee and colleagues.¹⁸

Methenamine mandelate

This agent is commonly used to prevent recurrent UTI, although there is a paucity of randomized, controlled trials to support its use. One such trial in patients with neurogenic bladder found that methenamine mandelate with acidification was superior to placebo (P <.02) for preventing UTI.¹⁹ Beyond this population, however, it’s difficult to assess methenamine’s efficacy in the prevention of recurrent UTI.

Methylene blue may be useful in the elderly

Methylene blue is a light-activated compound described as “photodynamic antimicrobial chemotherapy” (PACT). Once illuminated, it becomes a bactericide, causing excitation of electrons followed by one of two reactions:

• reduction oxidation
• formation of a labile singlet oxygen and then oxidation.

This makes resistance unlikely.

In an in vitro study, methylene blue was as effective as levofloxacin against Pseudomonas aeruginosa, Klebsiella pneumonia, Proteus mirabilis, Enterococcus, and Staphylococcus aureus when illuminated.

Potential benefits of this mode of treatment include local exposure and no drug interactions.

We suggest that methylene blue be placed and illuminated with a special catheter that would target UTI in the elderly population, among whom 52% of UTIs are associated with use of catheters.²⁰ In vivo effects, adverse effects, and cost are not known, which limits current applicability of this compound.

Vitamin C may reduce UTI in pregnancy

The proposed mechanism for the efficacy of vitamin C for the treatment of UTI is the acidification of urine, which is believed to reduce the proliferation of bacteria. However, several studies have shown that vitamin C, at various doses, does not reliably reduce urine pH.^15,21,22 Nonetheless, ascorbic acid was tested for its effect on UTI prevention during pregnancy.

In a single-blind trial, 110 pregnant women were divided into two groups (55 in each group):

• One group received ferrous sulfate (200 mg), folic acid (5 mg), and vitamin C (100 mg) daily for 3 months
• The other received ferrous sulfate (200 mg) and folic acid (5 mg) daily for 3 months.

Urine was cultured monthly. The incidence of UTI was significantly lower in the group receiving vitamin C (12.7%), compared with the control group (29.1%) (P=.03; odds ratio [OR], 0.35).²³

Uva ursi may have a prophylactic effect

Uva ursi (UVA-E) is one of the most commonly used herbal supplements for treatment of UTI. The crude extract from Bearberry or Arctostaphylos uva-ursi has been shown to act as an antimicrobial by decreasing bacterial adherence.²⁴ In addition, investigators have found the extract to have diuretic and anti-inflammatory properties.^25,26 However, few studies have explored its efficacy. One randomized, controlled trial that included 57 women (30 allocated to UVA-E and 27 to placebo) found a statistically significant reduction in the rate of recurrence at 1 year among women taking UVA-E, compared with those who did not.²⁷

Note that the women in this trial were given UVA-E for 1 month only. Long-term use of this herb has not been studied and may cause liver damage.

In a mouse model, forskolin reduced urinary-tract E. coli

This herb is derived from Indian coleus (Coleus forskohlii), a member of the mint family. It has been used primarily for its antiasthmatic, spasmolytic, and antihypertensive effects. It is believed to activate adenylate cyclase, increasing intracellular cyclic AMP (cAMP) concentrations and activating a number of key enzymatic pathways.²⁸

The findings of a recent observational study have spurred the use of forskolin in the treatment of recurrent UTI.²⁹ In the study, conducted on mice, when forskolin was injected into the bladder, intracellular E. coli decreased.

It is theorized that the incorporation of bacteria into intracellular vesicles of the bladder prevents exposure to antibiotics. When combined with an antibiotic, forskolin may increase bacterial elimination and thus lower the risk of recurrent infection. However, no randomized trials have evaluated the efficacy of this treatment.

Patients who are already taking antihypertensive medications should be cautious when using this herb, as it may lead to a drop in blood pressure.

Behavior changes are risk-free

One of the natural mechanisms that promotes bacterial elimination and prevents bacterial growth is urination. A recent review article on the subject found several contradictory studies on the effect of fluid intake on the risk of UTI.³⁰ Although there is no definitive evidence that susceptibility to UTI is linked to fluid intake, adequate hydration may reduce the risk of recurrent infection.

Similarly, voiding shortly after sexual intercourse may prevent UTI. One case-control study found a modest protective effect in patients who voided after intercourse.³¹

Clinical recommendations

Given the low risk of these measures, it seems reasonable to recommend postcoital voiding and increased fluid intake to prevent recurrent UTI.

A focus on symptoms

Phenazopyridine, the chemical found in numerous OTC medications, such as Pyridium, AZO, and Uristat, was discovered by Swiss chemist Bernhard Joos in the 1950s. Its mechanism of action is still unclear, but approximately 65% of the oral dose is excreted by the kidneys, where it has a direct topical analgesic effect.^32,33

Clinical recommendations

Patients should be warned that phenazopyridine will lead to orange urine discoloration.

The medication is generally well tolerated but should be used with caution in patients with acute renal failure, hemolytic anemia, or methemoglobinemia, as it may exacerbate these conditions.

Last words

Recurrent UTIs are common and impose a significant financial burden on our healthcare system. Although there are several antibiotic treatment options and dosing regimens available, increasing antibiotic resistance has made management of recurrent UTIs more difficult. Effective alternative treatments that reduce the reliance on antibiotics may minimize bacterial resistance and decrease the financial burden of this common condition.

CASE: Resolved

To reduce vaginal E. coli, the patient is started on vaginal estrogen cream. She is also advised to purchase cranberry tablets to help prevent future infections. Last, she is counseled about behavioral changes she can make and prescribed a short course of antibiotics to treat her culture-proven infection.

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