Changes in the sequence of RNA – also known as RNA editing – might contribute to the pathogenesis and prognosis of gastric cancer, investigators reported in the October issue of Gastroenterology.

By performing high-throughput transcriptome sequencing (or RNA-Seq) of gastric tumor tissue and cell lines, they identified “a clear RNA misediting phenotype” characterized by an imbalance in enzymes called adenosine deaminases that act on RNA, or ADAR, Tim Hon Man Chan, MD, of the National University of Singapore and his associates said. Normal gastric tissue did not show these changes, and they were associated with tumor progression and a poor prognosis, the investigators added.

Gastric cancer is the third most lethal malignancy worldwide. RNA editing in humans usually involves the conversion of adenosine-to-inosine (A-to-I), which is catalyzed by the ADAR1 and ADAR2 enzymes and has been linked to liver and esophageal cancer. To explore the role of A-to-I RNA editing in gastric cancer, the researchers performed next-generation sequencing transcriptomics of 14 tissue specimens from primary gastric tumors and 14 matched samples from noncancerous gastric tissue. They also sequenced gastric cancer cell lines and analyzed single nucleotide polymorphism array and RNA-Seq data from the gastric cancer datasets of The Cancer Genome Atlas (Gastroenterology. 2016 Jun 30. doi: 10.1053/j.gastro.2016.06.043). 

Compared with normal tissue specimens, almost all the samples of gastric cancers showed clear evidence of ADAR dysregulation – specifically, the gain of the ADAR1 gene and the loss of the ADAR2 gene, the researchers said. Furthermore, both the in vivo and in vitro studies indicated that RNA editing enabled ADAR1 to function as an oncogene in gastric cancer, while ADAR2 functioned as a tumor suppressor gene. In The Cancer Genome Atlas, about 36% of gastric cancer patients had gained ADAR1, while 44% of patients had lost ADAR2. Not only did these changes lead to a significant rise in ADAR1 mRNA expression and a significant decrease in ADAR2 mRNA expression, but patients with the most developed gastric tumors had the highest levels of ADAR1/ADAR2 dysregulation and the worst clinical prognosis, the investigators said.

SOURCE: American Gastroenterological Association

Additional tests of a model target gene called PODXL (podocalyxin-like) showed that ADAR2 regulates the editing of codon 241 such that histidine is replaced with arginine, which then neutralizes the normal tumorigenic ability of unedited or wild-type PODXL, the researchers reported. “Our data suggest that dysregulation of RNA editing is pervasive in gastric cancer, approaching levels reported for other types of epigenetic dysregulation including DNA methylation and histone modification,” they added. Taken together, the findings “highlight RNA editing as an important pathogenic mechanism in gastric carcinogenesis, and ADAR enzymes as potential gastric cancer therapeutic targets.” 

These findings are especially important because the identification of DNA mutations in gastric cancer has not led to viable therapies except for traztuzumab in ERBB2-positive gastric cancer and ramucirumab in advanced gastric cancer, the investigators said. “Our study demonstrates that differentially expressed ADARs in gastric tumors with consequent A-to-I RNA editing dysregulation may serve as a second layer of ‘somatic mutations’ and a novel contributor to gastric cancer,” they concluded.

The work was funded by the National Research Foundation Singapore, the Singapore Ministry of Education, and several other noncorporate entities. The researchers had no disclosures.
 

Changes in the sequence of RNA – also known as RNA editing – might contribute to the pathogenesis and prognosis of gastric cancer, investigators reported in the October issue of Gastroenterology.

By performing high-throughput transcriptome sequencing (or RNA-Seq) of gastric tumor tissue and cell lines, they identified “a clear RNA misediting phenotype” characterized by an imbalance in enzymes called adenosine deaminases that act on RNA, or ADAR, Tim Hon Man Chan, MD, of the National University of Singapore and his associates said. Normal gastric tissue did not show these changes, and they were associated with tumor progression and a poor prognosis, the investigators added.

Gastric cancer is the third most lethal malignancy worldwide. RNA editing in humans usually involves the conversion of adenosine-to-inosine (A-to-I), which is catalyzed by the ADAR1 and ADAR2 enzymes and has been linked to liver and esophageal cancer. To explore the role of A-to-I RNA editing in gastric cancer, the researchers performed next-generation sequencing transcriptomics of 14 tissue specimens from primary gastric tumors and 14 matched samples from noncancerous gastric tissue. They also sequenced gastric cancer cell lines and analyzed single nucleotide polymorphism array and RNA-Seq data from the gastric cancer datasets of The Cancer Genome Atlas (Gastroenterology. 2016 Jun 30. doi: 10.1053/j.gastro.2016.06.043). 

Compared with normal tissue specimens, almost all the samples of gastric cancers showed clear evidence of ADAR dysregulation – specifically, the gain of the ADAR1 gene and the loss of the ADAR2 gene, the researchers said. Furthermore, both the in vivo and in vitro studies indicated that RNA editing enabled ADAR1 to function as an oncogene in gastric cancer, while ADAR2 functioned as a tumor suppressor gene. In The Cancer Genome Atlas, about 36% of gastric cancer patients had gained ADAR1, while 44% of patients had lost ADAR2. Not only did these changes lead to a significant rise in ADAR1 mRNA expression and a significant decrease in ADAR2 mRNA expression, but patients with the most developed gastric tumors had the highest levels of ADAR1/ADAR2 dysregulation and the worst clinical prognosis, the investigators said.

SOURCE: American Gastroenterological Association

Additional tests of a model target gene called PODXL (podocalyxin-like) showed that ADAR2 regulates the editing of codon 241 such that histidine is replaced with arginine, which then neutralizes the normal tumorigenic ability of unedited or wild-type PODXL, the researchers reported. “Our data suggest that dysregulation of RNA editing is pervasive in gastric cancer, approaching levels reported for other types of epigenetic dysregulation including DNA methylation and histone modification,” they added. Taken together, the findings “highlight RNA editing as an important pathogenic mechanism in gastric carcinogenesis, and ADAR enzymes as potential gastric cancer therapeutic targets.” 

These findings are especially important because the identification of DNA mutations in gastric cancer has not led to viable therapies except for traztuzumab in ERBB2-positive gastric cancer and ramucirumab in advanced gastric cancer, the investigators said. “Our study demonstrates that differentially expressed ADARs in gastric tumors with consequent A-to-I RNA editing dysregulation may serve as a second layer of ‘somatic mutations’ and a novel contributor to gastric cancer,” they concluded.

The work was funded by the National Research Foundation Singapore, the Singapore Ministry of Education, and several other noncorporate entities. The researchers had no disclosures.
 

Changes in the sequence of RNA – also known as RNA editing – might contribute to the pathogenesis and prognosis of gastric cancer, investigators reported in the October issue of Gastroenterology.

By performing high-throughput transcriptome sequencing (or RNA-Seq) of gastric tumor tissue and cell lines, they identified “a clear RNA misediting phenotype” characterized by an imbalance in enzymes called adenosine deaminases that act on RNA, or ADAR, Tim Hon Man Chan, MD, of the National University of Singapore and his associates said. Normal gastric tissue did not show these changes, and they were associated with tumor progression and a poor prognosis, the investigators added.

Gastric cancer is the third most lethal malignancy worldwide. RNA editing in humans usually involves the conversion of adenosine-to-inosine (A-to-I), which is catalyzed by the ADAR1 and ADAR2 enzymes and has been linked to liver and esophageal cancer. To explore the role of A-to-I RNA editing in gastric cancer, the researchers performed next-generation sequencing transcriptomics of 14 tissue specimens from primary gastric tumors and 14 matched samples from noncancerous gastric tissue. They also sequenced gastric cancer cell lines and analyzed single nucleotide polymorphism array and RNA-Seq data from the gastric cancer datasets of The Cancer Genome Atlas (Gastroenterology. 2016 Jun 30. doi: 10.1053/j.gastro.2016.06.043). 

Compared with normal tissue specimens, almost all the samples of gastric cancers showed clear evidence of ADAR dysregulation – specifically, the gain of the ADAR1 gene and the loss of the ADAR2 gene, the researchers said. Furthermore, both the in vivo and in vitro studies indicated that RNA editing enabled ADAR1 to function as an oncogene in gastric cancer, while ADAR2 functioned as a tumor suppressor gene. In The Cancer Genome Atlas, about 36% of gastric cancer patients had gained ADAR1, while 44% of patients had lost ADAR2. Not only did these changes lead to a significant rise in ADAR1 mRNA expression and a significant decrease in ADAR2 mRNA expression, but patients with the most developed gastric tumors had the highest levels of ADAR1/ADAR2 dysregulation and the worst clinical prognosis, the investigators said.

SOURCE: American Gastroenterological Association

Additional tests of a model target gene called PODXL (podocalyxin-like) showed that ADAR2 regulates the editing of codon 241 such that histidine is replaced with arginine, which then neutralizes the normal tumorigenic ability of unedited or wild-type PODXL, the researchers reported. “Our data suggest that dysregulation of RNA editing is pervasive in gastric cancer, approaching levels reported for other types of epigenetic dysregulation including DNA methylation and histone modification,” they added. Taken together, the findings “highlight RNA editing as an important pathogenic mechanism in gastric carcinogenesis, and ADAR enzymes as potential gastric cancer therapeutic targets.” 

These findings are especially important because the identification of DNA mutations in gastric cancer has not led to viable therapies except for traztuzumab in ERBB2-positive gastric cancer and ramucirumab in advanced gastric cancer, the investigators said. “Our study demonstrates that differentially expressed ADARs in gastric tumors with consequent A-to-I RNA editing dysregulation may serve as a second layer of ‘somatic mutations’ and a novel contributor to gastric cancer,” they concluded.

The work was funded by the National Research Foundation Singapore, the Singapore Ministry of Education, and several other noncorporate entities. The researchers had no disclosures.
 

Treating inflammatory bowel disease with biologic therapies increases the risk of opportunistic infections but not the risk of serious infections, based on a systematic review and meta-analysis reported in the October issue of Clinical Gastroenterology and Hepatology.

Contrary to common belief, infection risk seemed similar with the integrin and anti–tumor necrosis factor classes, said Stefanos Bonovas, MD, MSc, PhD, of Humanitas Clinical and Research Center, Milan, with his associates. Clinicians and patients can use these findings to better weigh the risks and benefits of biologic therapies for IBD, although “studies in real-world settings, national and international registries, and clinical audits may serve as complementary data sources to further assess biologic treatments’ comparative and long-term safety profiles,” the researchers added.

Biologics can effectively manage IBD but raise concerns about infection and malignancy. To examine these risks in adults with IBD, the researchers systematically searched PubMed, Embase, Scopus, the Cochrane IBD Group Specialized Trials Register, the World Health Organization International Clinical Trials Registry Platform, and clinicaltrials.gov through March 2016 for randomized, placebo-controlled or head-to-head trials of approved IBD therapies, including adalimumab, certolizumab, golimumab, infliximab, natalizumab, and vedolizumab. After excluding systematic reviews, uncontrolled trials, and secondary analyses, 49 trials of 14,590 patients remained for meta-analysis, the investigators said (Clin Gastroenterol Hepatol. 2016 May 4. doi: 10.1016/j.cgh.2016.04.039).

Biologic therapy conferred a “moderate increase” in the likelihood of any infection, with an odds ratio of 1.19 when compared with patients who did not receive biologics (95% confidence interval, 1.10-1.29), the researchers said. The risk of opportunistic infections was somewhat higher (OR, 1.90; 95% CI, 1.21-3.01). However, biologic therapy did not significantly heighten the risk of serious infections, which most studies defined as infections leading to hospitalization, intravenous antibiotic treatment, or death (OR, 0.89; 95% CI, 0.71-1.12). “On the contrary, biologics appeared to significantly reduce risk of serious infections in studies with low risk of bias (OR, 0.56; 95% CI, 0.35-0.90),” the investigators wrote. They did not find an increased risk of malignancy with biologic therapy (OR, 0.90; 95% CI, 0.54-1.50), “but [these] data were insufficient in terms of exposure and follow-up times,” they added.

Comparisons of individual agents and classes also did not reveal any significant associations with the risk of infection, the investigators noted. They did acknowledge several limitations. None of the trials were head-to-head comparisons between biologics, and many were industry funded. Estimates of comparative harm were based on indirect comparisons, and therefore merited cautious interpretation. Because the trials were carried out for regulatory purposes, they enrolled highly selected and homogeneous cohorts of IBD patients, leading to underrepresentation of high-risk and elderly individuals, the researchers noted. “Finally, the exposure and follow-up times were up to 24 months, a time period that is considered sufficient when analyzing infectious adverse effects but wholly insufficient for cancer outcomes. With this in mind, we must look to large register-based cohort studies to enhance our understanding of the biologics-cancer association, despite the biases inherent in observational study designs.”

Dr. Bonovas had no disclosures, while three coauthors reported relationships with a number of pharmaceutical companies.

Treating inflammatory bowel disease with biologic therapies increases the risk of opportunistic infections but not the risk of serious infections, based on a systematic review and meta-analysis reported in the October issue of Clinical Gastroenterology and Hepatology.

Contrary to common belief, infection risk seemed similar with the integrin and anti–tumor necrosis factor classes, said Stefanos Bonovas, MD, MSc, PhD, of Humanitas Clinical and Research Center, Milan, with his associates. Clinicians and patients can use these findings to better weigh the risks and benefits of biologic therapies for IBD, although “studies in real-world settings, national and international registries, and clinical audits may serve as complementary data sources to further assess biologic treatments’ comparative and long-term safety profiles,” the researchers added.

Biologics can effectively manage IBD but raise concerns about infection and malignancy. To examine these risks in adults with IBD, the researchers systematically searched PubMed, Embase, Scopus, the Cochrane IBD Group Specialized Trials Register, the World Health Organization International Clinical Trials Registry Platform, and clinicaltrials.gov through March 2016 for randomized, placebo-controlled or head-to-head trials of approved IBD therapies, including adalimumab, certolizumab, golimumab, infliximab, natalizumab, and vedolizumab. After excluding systematic reviews, uncontrolled trials, and secondary analyses, 49 trials of 14,590 patients remained for meta-analysis, the investigators said (Clin Gastroenterol Hepatol. 2016 May 4. doi: 10.1016/j.cgh.2016.04.039).

Biologic therapy conferred a “moderate increase” in the likelihood of any infection, with an odds ratio of 1.19 when compared with patients who did not receive biologics (95% confidence interval, 1.10-1.29), the researchers said. The risk of opportunistic infections was somewhat higher (OR, 1.90; 95% CI, 1.21-3.01). However, biologic therapy did not significantly heighten the risk of serious infections, which most studies defined as infections leading to hospitalization, intravenous antibiotic treatment, or death (OR, 0.89; 95% CI, 0.71-1.12). “On the contrary, biologics appeared to significantly reduce risk of serious infections in studies with low risk of bias (OR, 0.56; 95% CI, 0.35-0.90),” the investigators wrote. They did not find an increased risk of malignancy with biologic therapy (OR, 0.90; 95% CI, 0.54-1.50), “but [these] data were insufficient in terms of exposure and follow-up times,” they added.

Comparisons of individual agents and classes also did not reveal any significant associations with the risk of infection, the investigators noted. They did acknowledge several limitations. None of the trials were head-to-head comparisons between biologics, and many were industry funded. Estimates of comparative harm were based on indirect comparisons, and therefore merited cautious interpretation. Because the trials were carried out for regulatory purposes, they enrolled highly selected and homogeneous cohorts of IBD patients, leading to underrepresentation of high-risk and elderly individuals, the researchers noted. “Finally, the exposure and follow-up times were up to 24 months, a time period that is considered sufficient when analyzing infectious adverse effects but wholly insufficient for cancer outcomes. With this in mind, we must look to large register-based cohort studies to enhance our understanding of the biologics-cancer association, despite the biases inherent in observational study designs.”

Dr. Bonovas had no disclosures, while three coauthors reported relationships with a number of pharmaceutical companies.

Treating inflammatory bowel disease with biologic therapies increases the risk of opportunistic infections but not the risk of serious infections, based on a systematic review and meta-analysis reported in the October issue of Clinical Gastroenterology and Hepatology.

Contrary to common belief, infection risk seemed similar with the integrin and anti–tumor necrosis factor classes, said Stefanos Bonovas, MD, MSc, PhD, of Humanitas Clinical and Research Center, Milan, with his associates. Clinicians and patients can use these findings to better weigh the risks and benefits of biologic therapies for IBD, although “studies in real-world settings, national and international registries, and clinical audits may serve as complementary data sources to further assess biologic treatments’ comparative and long-term safety profiles,” the researchers added.

Biologics can effectively manage IBD but raise concerns about infection and malignancy. To examine these risks in adults with IBD, the researchers systematically searched PubMed, Embase, Scopus, the Cochrane IBD Group Specialized Trials Register, the World Health Organization International Clinical Trials Registry Platform, and clinicaltrials.gov through March 2016 for randomized, placebo-controlled or head-to-head trials of approved IBD therapies, including adalimumab, certolizumab, golimumab, infliximab, natalizumab, and vedolizumab. After excluding systematic reviews, uncontrolled trials, and secondary analyses, 49 trials of 14,590 patients remained for meta-analysis, the investigators said (Clin Gastroenterol Hepatol. 2016 May 4. doi: 10.1016/j.cgh.2016.04.039).

Biologic therapy conferred a “moderate increase” in the likelihood of any infection, with an odds ratio of 1.19 when compared with patients who did not receive biologics (95% confidence interval, 1.10-1.29), the researchers said. The risk of opportunistic infections was somewhat higher (OR, 1.90; 95% CI, 1.21-3.01). However, biologic therapy did not significantly heighten the risk of serious infections, which most studies defined as infections leading to hospitalization, intravenous antibiotic treatment, or death (OR, 0.89; 95% CI, 0.71-1.12). “On the contrary, biologics appeared to significantly reduce risk of serious infections in studies with low risk of bias (OR, 0.56; 95% CI, 0.35-0.90),” the investigators wrote. They did not find an increased risk of malignancy with biologic therapy (OR, 0.90; 95% CI, 0.54-1.50), “but [these] data were insufficient in terms of exposure and follow-up times,” they added.

Comparisons of individual agents and classes also did not reveal any significant associations with the risk of infection, the investigators noted. They did acknowledge several limitations. None of the trials were head-to-head comparisons between biologics, and many were industry funded. Estimates of comparative harm were based on indirect comparisons, and therefore merited cautious interpretation. Because the trials were carried out for regulatory purposes, they enrolled highly selected and homogeneous cohorts of IBD patients, leading to underrepresentation of high-risk and elderly individuals, the researchers noted. “Finally, the exposure and follow-up times were up to 24 months, a time period that is considered sufficient when analyzing infectious adverse effects but wholly insufficient for cancer outcomes. With this in mind, we must look to large register-based cohort studies to enhance our understanding of the biologics-cancer association, despite the biases inherent in observational study designs.”

Dr. Bonovas had no disclosures, while three coauthors reported relationships with a number of pharmaceutical companies.

Regular physical exercise significantly improved measures of nonalcoholic fatty liver disease independently of dietary changes, according to a meta-analysis of randomized clinical trials published in the October issue of Clinical Gastroenterology and Hepatology.

“On the basis of the current findings, physical activity should be recommended not only in combination with dietary changes but also independently as an effective approach to manage NAFLD,” wrote Lorenzo Orci, MD, and his associates at the University of Geneva. “We propose that the level of evidence surrounding the specific role of physical activity in the management of NAFLD is now sufficient to be awarded a grade of Ia.”

Nonalcoholic fatty liver disease, “the hepatic manifestation of metabolic syndrome,” affects at least one in four U.S. adults and 15%-35% of individuals in Europe, the Middle East, China, and Japan, the researchers noted. Dietary changes are the cornerstone of NAFLD management, and there is less evidence for how physical exercise affects liver fat content. Therefore, the researchers searched MEDLINE, Embase, and the Cochrane databases from inception through October 2015 to find randomized trials of the impact of physical activity on markers of liver steatosis and liver inflammation in patients diagnosed with NAFLD, obesity, type 2 diabetes, or metabolic syndrome. This approach yielded 28 trials with data from more than 1,600 patients. Only two trials were multicenter, 13 required participants to have an NAFLD diagnosis, four focused on type 2 diabetes, and most of the rest included sedentary obese patients without requiring a diagnosis of NAFLD, the researchers said (Clin Gastroenterol Hepatol. 2016 May 4. doi: 10.1016/j.cgh.2016.04.036).

After researchers accounted for dietary changes, physical activity led to a significant drop in intrahepatic lipid content with a standardized mean difference of –0.69 compared with controls (95% confidence interval, –0.90 to –0.48; P less than .0001). “Because effect sizes such as standard mean difference [SMD] are difficult to interpret, the translation of such a statistical measure into a clinically relevant notion has been the focus of research for more than a decade,” the investigators added. “A commonly used interpretation was proposed by Cohen, who suggested that SMDs of 0.2, 0.5, and 0.8 correspond to small, moderate, and large effect sizes, respectively. By using this rule of thumb, our results indicate that physical activity exerts a moderate-to-large impact on the reduction of intrahepatic lipid content.”

Exercise reduced liver fat content even more in pediatric patients (SMD, –0.75; 95% CI, –0.1 to –0.5; P less than .0001) and in patients who had been specifically diagnosed with NAFLD (SMD, –0.86; 95% CI, –1.26 to –0.46; P less than .0001). Patients with the highest baseline body mass index also seemed to benefit more than patients with lower baseline BMI (P = .04). Indeed, exercise reduced BMI itself by a weighted mean difference of 0.8 (95% CI, –1.22 to 0.38; P less than .001), the researchers noted. Exercise intensity did not seem to affect the likelihood of benefit. There was a trend toward a greater effect of aerobic over resistance training (P = .06), and few studies examined the effects of combining both types of exercise.

The multivariable analysis also linked physical activity to an average 3.30 IU/L drop in alanine aminotransferase levels (95% CI, –5.57 to –1.04) and to a 4.9 IU/L decrease in aspartate aminotransferase levels (95% CI, –8.68 to –1.02). The investigators were unable to assess the long-term effects of physical exercise, nor its effects on hepatic fibrosis or inflammation, they noted. Nonetheless, the moderate to large effect size “provides strong evidence for the recommendation of physical activity as an effective intervention in the treatment of NAFLD,” they concluded. “Physical activity is also associated with an improvement in blood levels of aminotransferases and is particularly beneficial in patients presenting with severe obesity at baseline.”

The work was funded by the Ligue Genevoise contre le Cancer and the Dr Henri Dubois-Ferrière/Dinu Lipatti Foundation and by the Swiss National Science Foundation. The investigators had no disclosures.

Regular physical exercise significantly improved measures of nonalcoholic fatty liver disease independently of dietary changes, according to a meta-analysis of randomized clinical trials published in the October issue of Clinical Gastroenterology and Hepatology.

“On the basis of the current findings, physical activity should be recommended not only in combination with dietary changes but also independently as an effective approach to manage NAFLD,” wrote Lorenzo Orci, MD, and his associates at the University of Geneva. “We propose that the level of evidence surrounding the specific role of physical activity in the management of NAFLD is now sufficient to be awarded a grade of Ia.”

Nonalcoholic fatty liver disease, “the hepatic manifestation of metabolic syndrome,” affects at least one in four U.S. adults and 15%-35% of individuals in Europe, the Middle East, China, and Japan, the researchers noted. Dietary changes are the cornerstone of NAFLD management, and there is less evidence for how physical exercise affects liver fat content. Therefore, the researchers searched MEDLINE, Embase, and the Cochrane databases from inception through October 2015 to find randomized trials of the impact of physical activity on markers of liver steatosis and liver inflammation in patients diagnosed with NAFLD, obesity, type 2 diabetes, or metabolic syndrome. This approach yielded 28 trials with data from more than 1,600 patients. Only two trials were multicenter, 13 required participants to have an NAFLD diagnosis, four focused on type 2 diabetes, and most of the rest included sedentary obese patients without requiring a diagnosis of NAFLD, the researchers said (Clin Gastroenterol Hepatol. 2016 May 4. doi: 10.1016/j.cgh.2016.04.036).

After researchers accounted for dietary changes, physical activity led to a significant drop in intrahepatic lipid content with a standardized mean difference of –0.69 compared with controls (95% confidence interval, –0.90 to –0.48; P less than .0001). “Because effect sizes such as standard mean difference [SMD] are difficult to interpret, the translation of such a statistical measure into a clinically relevant notion has been the focus of research for more than a decade,” the investigators added. “A commonly used interpretation was proposed by Cohen, who suggested that SMDs of 0.2, 0.5, and 0.8 correspond to small, moderate, and large effect sizes, respectively. By using this rule of thumb, our results indicate that physical activity exerts a moderate-to-large impact on the reduction of intrahepatic lipid content.”

Exercise reduced liver fat content even more in pediatric patients (SMD, –0.75; 95% CI, –0.1 to –0.5; P less than .0001) and in patients who had been specifically diagnosed with NAFLD (SMD, –0.86; 95% CI, –1.26 to –0.46; P less than .0001). Patients with the highest baseline body mass index also seemed to benefit more than patients with lower baseline BMI (P = .04). Indeed, exercise reduced BMI itself by a weighted mean difference of 0.8 (95% CI, –1.22 to 0.38; P less than .001), the researchers noted. Exercise intensity did not seem to affect the likelihood of benefit. There was a trend toward a greater effect of aerobic over resistance training (P = .06), and few studies examined the effects of combining both types of exercise.

The multivariable analysis also linked physical activity to an average 3.30 IU/L drop in alanine aminotransferase levels (95% CI, –5.57 to –1.04) and to a 4.9 IU/L decrease in aspartate aminotransferase levels (95% CI, –8.68 to –1.02). The investigators were unable to assess the long-term effects of physical exercise, nor its effects on hepatic fibrosis or inflammation, they noted. Nonetheless, the moderate to large effect size “provides strong evidence for the recommendation of physical activity as an effective intervention in the treatment of NAFLD,” they concluded. “Physical activity is also associated with an improvement in blood levels of aminotransferases and is particularly beneficial in patients presenting with severe obesity at baseline.”

The work was funded by the Ligue Genevoise contre le Cancer and the Dr Henri Dubois-Ferrière/Dinu Lipatti Foundation and by the Swiss National Science Foundation. The investigators had no disclosures.

Regular physical exercise significantly improved measures of nonalcoholic fatty liver disease independently of dietary changes, according to a meta-analysis of randomized clinical trials published in the October issue of Clinical Gastroenterology and Hepatology.

“On the basis of the current findings, physical activity should be recommended not only in combination with dietary changes but also independently as an effective approach to manage NAFLD,” wrote Lorenzo Orci, MD, and his associates at the University of Geneva. “We propose that the level of evidence surrounding the specific role of physical activity in the management of NAFLD is now sufficient to be awarded a grade of Ia.”

Nonalcoholic fatty liver disease, “the hepatic manifestation of metabolic syndrome,” affects at least one in four U.S. adults and 15%-35% of individuals in Europe, the Middle East, China, and Japan, the researchers noted. Dietary changes are the cornerstone of NAFLD management, and there is less evidence for how physical exercise affects liver fat content. Therefore, the researchers searched MEDLINE, Embase, and the Cochrane databases from inception through October 2015 to find randomized trials of the impact of physical activity on markers of liver steatosis and liver inflammation in patients diagnosed with NAFLD, obesity, type 2 diabetes, or metabolic syndrome. This approach yielded 28 trials with data from more than 1,600 patients. Only two trials were multicenter, 13 required participants to have an NAFLD diagnosis, four focused on type 2 diabetes, and most of the rest included sedentary obese patients without requiring a diagnosis of NAFLD, the researchers said (Clin Gastroenterol Hepatol. 2016 May 4. doi: 10.1016/j.cgh.2016.04.036).

After researchers accounted for dietary changes, physical activity led to a significant drop in intrahepatic lipid content with a standardized mean difference of –0.69 compared with controls (95% confidence interval, –0.90 to –0.48; P less than .0001). “Because effect sizes such as standard mean difference [SMD] are difficult to interpret, the translation of such a statistical measure into a clinically relevant notion has been the focus of research for more than a decade,” the investigators added. “A commonly used interpretation was proposed by Cohen, who suggested that SMDs of 0.2, 0.5, and 0.8 correspond to small, moderate, and large effect sizes, respectively. By using this rule of thumb, our results indicate that physical activity exerts a moderate-to-large impact on the reduction of intrahepatic lipid content.”

Exercise reduced liver fat content even more in pediatric patients (SMD, –0.75; 95% CI, –0.1 to –0.5; P less than .0001) and in patients who had been specifically diagnosed with NAFLD (SMD, –0.86; 95% CI, –1.26 to –0.46; P less than .0001). Patients with the highest baseline body mass index also seemed to benefit more than patients with lower baseline BMI (P = .04). Indeed, exercise reduced BMI itself by a weighted mean difference of 0.8 (95% CI, –1.22 to 0.38; P less than .001), the researchers noted. Exercise intensity did not seem to affect the likelihood of benefit. There was a trend toward a greater effect of aerobic over resistance training (P = .06), and few studies examined the effects of combining both types of exercise.

The multivariable analysis also linked physical activity to an average 3.30 IU/L drop in alanine aminotransferase levels (95% CI, –5.57 to –1.04) and to a 4.9 IU/L decrease in aspartate aminotransferase levels (95% CI, –8.68 to –1.02). The investigators were unable to assess the long-term effects of physical exercise, nor its effects on hepatic fibrosis or inflammation, they noted. Nonetheless, the moderate to large effect size “provides strong evidence for the recommendation of physical activity as an effective intervention in the treatment of NAFLD,” they concluded. “Physical activity is also associated with an improvement in blood levels of aminotransferases and is particularly beneficial in patients presenting with severe obesity at baseline.”

The work was funded by the Ligue Genevoise contre le Cancer and the Dr Henri Dubois-Ferrière/Dinu Lipatti Foundation and by the Swiss National Science Foundation. The investigators had no disclosures.

Differentiating the irritable, oppositional child with attention-deficit/hyperactivity disorder (ADHD) from the child with bipolar disorder (BD) often is difficult. To make matters more complicated, 50% to 70% of patients with BD have comorbid ADHD.^1,2 Accordingly, clinicians are often faced with the moody, irritable, dis­ruptive child whose parents want to know if he (she) is “bipolar” to try to deal with oppositional and mood behaviors.

In this article, we present an approach that will help you distinguish these 2 disorders from each other.

Precision medicineThere is a lack of evidence-based methods for diagnosing psychiat­ric disorders in children and adolescents. DSM-5 provides clinicians with diagnostic checklists that rely on the clinician’s judgment and training in evaluating a patient.³ In The innovator’s prescription: a dis­ruptive solution for health care, Christensen et al⁴ describe how medi­cine is moving from “intuitive medicine” to empirical medicine and toward “precision medicine.” Intuitive medicine depends on the clini­cian’s expertise, training, and exposure to different disorders, which is the traditional clinical model that predominates in child psychiatry. Empirical medicine relies on laboratory results, scans, scales, and other standardized tools.

Precision medicine occurs when a disorder can be precisely diag­nosed and its cause understood, and when it can be treated with effec­tive, evidence-based therapies. An example of this movement toward precision is Timothy syndrome (TS), a rare autosomal dominant disorder characterized by physical malformations, cardiac arrhyth­mias and structural heart defects, webbing of fingers and toes, and autism spectrum disorder. In the past, a child with TS would have been given a diagnosis of intellectual disability, or a specialist in developmental disorders might recognize the pattern of TS. It is now known that TS is caused by muta­tions in CACNA1C, the gene encoding the calcium channel Ca_v1.2α subunit, allowing precise diagnosis by genotyping.⁵

Although there are several tools that help clinicians assess symptoms of ADHD and BD, including rating scales such the Vanderbilt ADHD Diagnostic Rating Scale and Young Mania Rating Scale, none of these scales are diagnostic. Youngstrom et al^6,7 have developed an evidence-based strategy to diagnose pediatric BD. This method uses a nomogram that takes into account the base rate of BD in a clinical set­ting and family history of BD.

We will describe and contrast the epi­demiologic and clinical characteristics of pediatric BD from ADHD and use the Youngstrom nomogram to better define these patients. Although still far from pre­cision medicine, the type of approach rep­resents an ongoing effort in mental health care to increase diagnostic accuracy and improve treatment outcomes.

Pediatric bipolar disorder
Prevalence of pediatric BD is 1.8% (95% CI, 1.1% to 3.0%),⁸ which does not include sub-threshold cases of BD. ADHD and oppo­sitional defiant disorder (ODD) are 8 to 10 times more prevalent. For the purposes of the nomogram, the “base rate” is the rate at which a disorder occurs in different clinical settings. In general outpatient clinics, BD might occur 6% to 8% of the time, whereas in a county-run child psychiatry inpatient facility the rate is 11%.⁶ A reasonable rate in an outpatient pediatric setting is 6%.

Family history. In the Bipolar Offspring Study,9 the rate of BD in children of par­ents with BD was 13 times greater than that of controls, and the rate of anxiety and behavior disorders was approximately twice that of children of parents without BD (Table 1).⁹ This study evaluated 388 children of 233 parents with BD and 251 children of 143 demographically matched controls.

Elevated or expansive mood. The child might have a mood that is inappropriately giddy, silly, elated, or euphoric. Often this mood will be present without reason and last for several hours. It may be distin­guished from a transient cheerful mood by the intensity and duration of the episode. The child with BD may have little to no insight about the inappropriate nature of their elevated mood, when present. 

Irritable mood. The child might become markedly belligerent or irritated with intense outbursts of anger, 2 to 3 times a day for several hours. An adolescent might appear extremely oppositional, belliger­ent, or hostile with parents and others. 

Grandiosity or inflated self-esteem can be confused with brief childhood fanta­sies of increased capability. Typically, true grandiosity can manifest as assertion of great competency in all areas of life, which usually cannot be altered by contrary exter­nal evidence. Occasionally, this is bizarre and includes delusions of “super powers.” The child in a manic episode will not only assert that she can fly, but will jump off the garage roof to prove it. 

Decreased need for sleep. The child may only require 4 to 5 hours of sleep a night during a manic episode without feeling fatigued or showing evidence of tiredness. Consider substance use in this differential diagnosis, especially in adolescents.

Increased talkativeness. Lack of inhibi­tion to social norms may lead pediatric BD patients to blurt out answers during class or repeatedly be disciplined for talking to peers in class. Speech typically is rapid and pressured to the point where it might be continuous and seems to jump between loosely related subjects.

Flight of ideas or racing thoughts. The child or adolescent might report a subjec­tive feeling that his thoughts are moving so rapidly that his speech cannot keep up. Often this is differentiated from rapid speech by the degree of rapidity the patient expresses loosely related topics that might seem completely unrelated to the listener.

Distractibility, short attention span. During a manic episode, the child or ado­lescent might report that it is impossible to pay attention to class or other outside events because of rapidly changing focus of their thoughts. This symptom must be care­fully distinguished from the distractibility and inattention of ADHD, which typically is a more fixed and long-standing pattern rather than a brief episodic phenomenon in a manic or hypomanic episode.

Increase in goal-directed activity. During a mild manic episode, the child or adoles­cent may be capable of accomplishing a great deal of work. However, episodes that are more severe manifest as an individual starting numerous ambitious projects that she later is unable to complete.

Excessive risk-taking activities. The child or adolescent might become involved in forbidden, pleasurable activities that have a high risk of adverse consequences. This can manifest as hypersexual behavior, fre­quent fighting, increased recklessness, use of drugs and alcohol, shopping sprees, and reckless driving.

There are few studies comparing patients with comorbid BD and ADHD with patients with only ADHD. Geller et al¹¹ compared 60 children with BD and ADHD (mean age, 10) to age- and sex-matched patients with ADHD and no mood disorder. Compared with children who had ADHD, those with BD exhib­ited significantly greater elevated mood, grandiosity, flight and/or racing of ideas, decreased need for sleep, and hypersexual­ity (Figure 1,¹¹). Features common to both groups—and therefore not useful in differentiating the disorders—included irritability, hyperactivity, accelerated speech, and distractibility.
 

CASE REPORTIrritable and disruptiveBill, age 12, has been brought to see you by his mother because she is concerned about escalating behavior problems at home and school in the past several months. The school principal has called her about his obnoxious behavior with teachers and about other par­ents’ complaints that he has made unwanted sexual advances to girls who sit next to him in class.

Bill, who is in the 7th grade, is on the verge of being suspended for his inappropriate and disruptive behavior. His parents report that he is irritable around them and stays up all night, messaging his friends on the Internet from his iPad in his bedroom. They attribute his inappro­priate sexual behavior to puberty and possibly to the Web sites he views.

Bill’s mother is concerned about his:
   • increasing behavior problems during the last several months at home and school
   • intensifying irritability and depressive symptoms
   • staying up all night on the Internet, phoning friends, and doing projects
   • frequent unprovoked, outbursts of rage occurring with increasing frequency and intensity (almost daily)
   • moderate grandiosity, including telling the soccer coach and teachers how to do their jobs
   • inappropriate sexual behavior, including kissing and touching female classmates.

During your history, you learn that Bill has been a bright and artistic child, with good academic performance. His peer relation­ships have been satisfactory, but not excel­lent—he tends to be “bossy” with his peers. He is medically healthy and not taking any medications. As part of your history, you also talk with Bill and his family about exposure to trauma or significant stressors, which they deny. You learn that Bill’s father was diag­nosed with BD I at age 32.

Completing the nomogram developed by Youngstrom et al^6,7 using these variables (see this article at CurrentPsychiatry.com for Figure 2)^6,7 gives Bill a post-test probability of approximately 42%. The threshold for moving ahead with assessment and possible treat­ment, the “test-treatment threshold,” depends on your clinical setting.^12,13 Our clinical expe­rience is that, when the post-test probability exceeds 30%, further assessment for BD is warranted.

The next strategy is to look at Bill’s scores on externalizing behaviors using an instru­ment such as the Vanderbilt ADHD Diagnostic Parent Rating Scale. Few pediatric patients with BD will score low on externalizing behaviors.14 Bill scores in the clinically signifi­cant range for hyperactivity/impulsivity and positive on the screeners for ODD, conduct disorder (CD), and anxiety/depression.

You decide that Bill is at high risk of pedi­atric BD; he has a post-test probability of approximately 45%, and many externalizing behaviors on the Vanderbilt. You give Bill a diagnosis of BD I and ADHD and prescribe ris­peridone, 0.5 mg/d, which results in signifi­cant improvement in mood swings and other manic behaviors.

ADHD
Epidemiology. ADHD is one of the most common neurodevelopmental disorders in childhood, with prevalence estimates of 8% of U.S. children.^15,16 Overall, boys are more likely to be assigned a diagnosis of ADHD than girls.¹⁵ Although ADHD often is diagnosed in early childhood, research is working to clarify the lifetime preva­lence of ADHD into late adolescence and adulthood. Current estimates suggest that ADHD persists into adulthood in close to two-thirds of patients.¹⁷ However, the symptom presentation can change during adolescence and adulthood, with less overt hyperactivity and symptoms of impulsivity transitioning to risky behaviors involving trouble with the law, substance use, and sexual promiscuity.¹⁷

As in pediatric BD, comorbidity is com­mon in ADHD, with uncomplicated ADHD being the exception rather than the rule. Recent studies have suggested that approx­imately two-thirds of children who have a diagnosis of ADHD have ≥1 comorbid diag­noses.¹⁵ Common comorbidities are similar to those seen in BD, including ODD, CD, anxiety disorders, depression, and learning disability. Several tools and resources are available to help clinicians navigate these issues within their practices.

Family history. Genetics appear to play a large role in ADHD, with twin studies suggesting inheritance of approximately 76%.18 Environmental factors contribute, either in the development of ADHD or in the exacerbation of an underlying familial predisposition. Interestingly, in children with BD, family history often is significant for several family members who have both ADHD and BD. However, in children with ADHD only, family history often reflects an absence of family members with BD.19 Although not diagnostic, this pattern can be helpful when considering a diagnosis of BD vs ADHD.

Clinical picture. ADHD often is recog­nized in childhood; DSM-5 criteria spec­ify that symptoms be present before age 12 and persist for at least 6 months. This characterization of the timing of symp­toms helps exclude behavioral disruptions related to external factors such as trauma (eg, death of a caregiver) or abuse. It also is important to note that symptoms might be present earlier but not come to attention clinically until a later age, perhaps because of increasing demands placed on the child by school, peer groups, and extracurricu­lar activities. To make an ADHD diag­nosis, symptoms must be present in >1 setting and interfere with functioning or development.

Core symptoms of ADHD include inat­tention, hyperactivity, and impulsivity that are out of proportion to the child’s developmental level (Table 2).20 When considering diagnosis of ADHD, 6 of 9 symptoms for inattention and/or hyperactivity-impulsivity must be present at a clinically significant level.

Three different ADHD presentations are recognized: combined, inattentive, and hyperactive impulsive. Children with predominant impulsive and hyperactive behaviors generally come to clinical atten­tion at a younger age; inattentive symptoms often take longer to identify.

Children with ADHD have been noted to have lower tolerance for frustration, which might make anger outbursts and aggressive behavior more likely. Anger and aggression in ADHD often stem from impulsivity, rather than irritable mood seen with BD.18 Issues related to self-esteem, depression, substance use, and CD can contribute to symptoms of irrita­bility, anger, and aggression that can occur in children with ADHD. Although these symptoms can overlap with those seen in children with BD, other core symptoms of ADHD will not be present.

ODD is one of the most common comor­bidities among children with ADHD, and the combination of ODD and ADHD may be confused with BD. Children with ODD often are noted to exhibit a pattern of negative and defiant behavior that is out of proportion to what is seen in their peers and for their age and develop­mental level (Table 3).²⁰ When considering an ODD diagnosis, 4 out of 8 symptoms must be present at a clinically significant level.

The following case highlights the poten­tial similarities between ADHD/ODD and BD, with tips on how to distinguish them.

CASE REPORT

Angry and destructiveSam, age 7, has been given a diagnosis of ADHD, but his parents think that he isn’t improving with methylphenidate treatment. They are concerned that he has anger issues like his uncle, who has “bipolar disorder.”

Sam’s parents find that he gets frustrated easily and note that he has frequent short “meltdowns” and “mood swings.” During these episodes he yells, is aggressive towards others, and can be destructive. They are concerned because Sam will become angry quickly, then act as if nothing happened after the meltdown has blown over. Sam’s parents feel that he doesn’t listen to them and often argues when they make a request. His parents note that when they push harder, Sam digs in his heels, which can trigger his meltdowns.

Despite clearly disobeying his parents, Sam often says that things aren’t his fault and blames his parents or siblings instead. Sam seems to disagree with people often. His mother reports “if I say the water looks blue, he’ll say it’s green.” Often, Sam seems to argue or pester others to get a rise out of them. This is causing problems for Sam with his siblings and peers, and significant stress for his parents. Family history suggests that Sam’s uncle may have ADHD with CD or a substance use disorder, rather than true BD. Other than Sam’s uncle, there is no family his­tory for BD.

Sam’s parents say that extended release methylphenidate, 20 mg/d, has helped with hyperactivity, but they are concerned that other symptoms have not improved. Aside from the symptoms listed above, Sam is described as a happy child. There is no his­tory of trauma, and no symptoms of anxiety are noted. Sam sometimes gets “down” when things don’t go his way, but this lasts only for a few hours. Sam has a history of delayed sleep onset, which responded well to melato­nin. No other symptoms that suggest mania are described.

You complete the pediatric bipolar nomo­gram (Figure 3)^6,7 and Sam’s parents com­plete a Vanderbilt ADHD Diagnostic Parent Rating Scale. At first, Sam seems to have sev­eral factors that might indicate BD: aggres­sive behavior, mood swings, sleep problems, and, possibly, a family history of BD.

However, a careful history provides several clues that Sam has a comorbid diagnosis of ODD. Sam is exhibiting the classic pattern of negativist behavior seen in children with ODD. In contrast to the episodic pattern of BD, these symptoms are prevalent and per­sistent, and manifest as an overall pattern of functioning. Impulsivity seen in children with ADHD can complicate the picture, but again appears as a consistent pattern rather than bouts of irritability. Sam’s core symptoms of ADHD (hyperactivity) improved with methyl­phenidate, but the underlying symptoms of ODD persisted.

Sleep problems are common in chil­dren who have ADHD and BD, but Sam’s delayed sleep onset responded to melato­nin, whereas the insomnia seen in BD often is refractory to lower-intensity interven­tions, such as melatonin. Taking a careful family history led you to believe that BD in the family is unlikely. Although this type of detail may not always be available, it can be helpful to ask about mental health symptoms that seem to “run in the family.”

Bottom Line

Distinguishing the child who has bipolar disorder from one who has attention-deficit/hyperactivity disorder can be challenging. A careful history helps ensure that you are on the path toward understanding the diagnostic possibilities. Tools such as the Vanderbilt Rating Scale can further clarify possible diagnoses, and the nomogram approach can provide even more predictive information when considering a diagnosis of bipolar disorder.

Related Resources
• Children and Adults with Attention Deficit/Hyperactivity Disorder (CHADD). www.chadd.org.
• American Academy of Child and Adolescent Psychiatry. Facts for Families. www.aacap.org/cs/root/facts_for_families/ facts_for_families.
• Froehlich TE, Delgado SV, Anixt JS. Expanding medica­tion options for pediatric ADHD. Current Psychiatry. 2013;(12)12:20-29.
• Passarotti AM, Pavuluri MN. Brain functional domains in­form therapeutic interventions in attention-deficit/hyper­activity disorder and pediatric bipolar disorder. Expert Rev Neurother. 2011;11(6):897-914.

Drug Brand Names
Methylphenidate • Ritalin,  Methylin, Metadate CD, Metadate ER, Methylin ER, Ritalin LA, Ritalin SR, Concerta, Quillivant XR, Daytrana

Risperidone • Risperdal

Differentiating the irritable, oppositional child with attention-deficit/hyperactivity disorder (ADHD) from the child with bipolar disorder (BD) often is difficult. To make matters more complicated, 50% to 70% of patients with BD have comorbid ADHD.^1,2 Accordingly, clinicians are often faced with the moody, irritable, dis­ruptive child whose parents want to know if he (she) is “bipolar” to try to deal with oppositional and mood behaviors.

In this article, we present an approach that will help you distinguish these 2 disorders from each other.

Precision medicineThere is a lack of evidence-based methods for diagnosing psychiat­ric disorders in children and adolescents. DSM-5 provides clinicians with diagnostic checklists that rely on the clinician’s judgment and training in evaluating a patient.³ In The innovator’s prescription: a dis­ruptive solution for health care, Christensen et al⁴ describe how medi­cine is moving from “intuitive medicine” to empirical medicine and toward “precision medicine.” Intuitive medicine depends on the clini­cian’s expertise, training, and exposure to different disorders, which is the traditional clinical model that predominates in child psychiatry. Empirical medicine relies on laboratory results, scans, scales, and other standardized tools.

Precision medicine occurs when a disorder can be precisely diag­nosed and its cause understood, and when it can be treated with effec­tive, evidence-based therapies. An example of this movement toward precision is Timothy syndrome (TS), a rare autosomal dominant disorder characterized by physical malformations, cardiac arrhyth­mias and structural heart defects, webbing of fingers and toes, and autism spectrum disorder. In the past, a child with TS would have been given a diagnosis of intellectual disability, or a specialist in developmental disorders might recognize the pattern of TS. It is now known that TS is caused by muta­tions in CACNA1C, the gene encoding the calcium channel Ca_v1.2α subunit, allowing precise diagnosis by genotyping.⁵

Although there are several tools that help clinicians assess symptoms of ADHD and BD, including rating scales such the Vanderbilt ADHD Diagnostic Rating Scale and Young Mania Rating Scale, none of these scales are diagnostic. Youngstrom et al^6,7 have developed an evidence-based strategy to diagnose pediatric BD. This method uses a nomogram that takes into account the base rate of BD in a clinical set­ting and family history of BD.

We will describe and contrast the epi­demiologic and clinical characteristics of pediatric BD from ADHD and use the Youngstrom nomogram to better define these patients. Although still far from pre­cision medicine, the type of approach rep­resents an ongoing effort in mental health care to increase diagnostic accuracy and improve treatment outcomes.

Pediatric bipolar disorder
Prevalence of pediatric BD is 1.8% (95% CI, 1.1% to 3.0%),⁸ which does not include sub-threshold cases of BD. ADHD and oppo­sitional defiant disorder (ODD) are 8 to 10 times more prevalent. For the purposes of the nomogram, the “base rate” is the rate at which a disorder occurs in different clinical settings. In general outpatient clinics, BD might occur 6% to 8% of the time, whereas in a county-run child psychiatry inpatient facility the rate is 11%.⁶ A reasonable rate in an outpatient pediatric setting is 6%.

Family history. In the Bipolar Offspring Study,9 the rate of BD in children of par­ents with BD was 13 times greater than that of controls, and the rate of anxiety and behavior disorders was approximately twice that of children of parents without BD (Table 1).⁹ This study evaluated 388 children of 233 parents with BD and 251 children of 143 demographically matched controls.

Elevated or expansive mood. The child might have a mood that is inappropriately giddy, silly, elated, or euphoric. Often this mood will be present without reason and last for several hours. It may be distin­guished from a transient cheerful mood by the intensity and duration of the episode. The child with BD may have little to no insight about the inappropriate nature of their elevated mood, when present. 

Irritable mood. The child might become markedly belligerent or irritated with intense outbursts of anger, 2 to 3 times a day for several hours. An adolescent might appear extremely oppositional, belliger­ent, or hostile with parents and others. 

Grandiosity or inflated self-esteem can be confused with brief childhood fanta­sies of increased capability. Typically, true grandiosity can manifest as assertion of great competency in all areas of life, which usually cannot be altered by contrary exter­nal evidence. Occasionally, this is bizarre and includes delusions of “super powers.” The child in a manic episode will not only assert that she can fly, but will jump off the garage roof to prove it. 

Decreased need for sleep. The child may only require 4 to 5 hours of sleep a night during a manic episode without feeling fatigued or showing evidence of tiredness. Consider substance use in this differential diagnosis, especially in adolescents.

Increased talkativeness. Lack of inhibi­tion to social norms may lead pediatric BD patients to blurt out answers during class or repeatedly be disciplined for talking to peers in class. Speech typically is rapid and pressured to the point where it might be continuous and seems to jump between loosely related subjects.

Flight of ideas or racing thoughts. The child or adolescent might report a subjec­tive feeling that his thoughts are moving so rapidly that his speech cannot keep up. Often this is differentiated from rapid speech by the degree of rapidity the patient expresses loosely related topics that might seem completely unrelated to the listener.

Distractibility, short attention span. During a manic episode, the child or ado­lescent might report that it is impossible to pay attention to class or other outside events because of rapidly changing focus of their thoughts. This symptom must be care­fully distinguished from the distractibility and inattention of ADHD, which typically is a more fixed and long-standing pattern rather than a brief episodic phenomenon in a manic or hypomanic episode.

Increase in goal-directed activity. During a mild manic episode, the child or adoles­cent may be capable of accomplishing a great deal of work. However, episodes that are more severe manifest as an individual starting numerous ambitious projects that she later is unable to complete.

Excessive risk-taking activities. The child or adolescent might become involved in forbidden, pleasurable activities that have a high risk of adverse consequences. This can manifest as hypersexual behavior, fre­quent fighting, increased recklessness, use of drugs and alcohol, shopping sprees, and reckless driving.

There are few studies comparing patients with comorbid BD and ADHD with patients with only ADHD. Geller et al¹¹ compared 60 children with BD and ADHD (mean age, 10) to age- and sex-matched patients with ADHD and no mood disorder. Compared with children who had ADHD, those with BD exhib­ited significantly greater elevated mood, grandiosity, flight and/or racing of ideas, decreased need for sleep, and hypersexual­ity (Figure 1,¹¹). Features common to both groups—and therefore not useful in differentiating the disorders—included irritability, hyperactivity, accelerated speech, and distractibility.
 

CASE REPORTIrritable and disruptiveBill, age 12, has been brought to see you by his mother because she is concerned about escalating behavior problems at home and school in the past several months. The school principal has called her about his obnoxious behavior with teachers and about other par­ents’ complaints that he has made unwanted sexual advances to girls who sit next to him in class.

Bill, who is in the 7th grade, is on the verge of being suspended for his inappropriate and disruptive behavior. His parents report that he is irritable around them and stays up all night, messaging his friends on the Internet from his iPad in his bedroom. They attribute his inappro­priate sexual behavior to puberty and possibly to the Web sites he views.

Bill’s mother is concerned about his:
   • increasing behavior problems during the last several months at home and school
   • intensifying irritability and depressive symptoms
   • staying up all night on the Internet, phoning friends, and doing projects
   • frequent unprovoked, outbursts of rage occurring with increasing frequency and intensity (almost daily)
   • moderate grandiosity, including telling the soccer coach and teachers how to do their jobs
   • inappropriate sexual behavior, including kissing and touching female classmates.

During your history, you learn that Bill has been a bright and artistic child, with good academic performance. His peer relation­ships have been satisfactory, but not excel­lent—he tends to be “bossy” with his peers. He is medically healthy and not taking any medications. As part of your history, you also talk with Bill and his family about exposure to trauma or significant stressors, which they deny. You learn that Bill’s father was diag­nosed with BD I at age 32.

Completing the nomogram developed by Youngstrom et al^6,7 using these variables (see this article at CurrentPsychiatry.com for Figure 2)^6,7 gives Bill a post-test probability of approximately 42%. The threshold for moving ahead with assessment and possible treat­ment, the “test-treatment threshold,” depends on your clinical setting.^12,13 Our clinical expe­rience is that, when the post-test probability exceeds 30%, further assessment for BD is warranted.

The next strategy is to look at Bill’s scores on externalizing behaviors using an instru­ment such as the Vanderbilt ADHD Diagnostic Parent Rating Scale. Few pediatric patients with BD will score low on externalizing behaviors.14 Bill scores in the clinically signifi­cant range for hyperactivity/impulsivity and positive on the screeners for ODD, conduct disorder (CD), and anxiety/depression.

You decide that Bill is at high risk of pedi­atric BD; he has a post-test probability of approximately 45%, and many externalizing behaviors on the Vanderbilt. You give Bill a diagnosis of BD I and ADHD and prescribe ris­peridone, 0.5 mg/d, which results in signifi­cant improvement in mood swings and other manic behaviors.

ADHD
Epidemiology. ADHD is one of the most common neurodevelopmental disorders in childhood, with prevalence estimates of 8% of U.S. children.^15,16 Overall, boys are more likely to be assigned a diagnosis of ADHD than girls.¹⁵ Although ADHD often is diagnosed in early childhood, research is working to clarify the lifetime preva­lence of ADHD into late adolescence and adulthood. Current estimates suggest that ADHD persists into adulthood in close to two-thirds of patients.¹⁷ However, the symptom presentation can change during adolescence and adulthood, with less overt hyperactivity and symptoms of impulsivity transitioning to risky behaviors involving trouble with the law, substance use, and sexual promiscuity.¹⁷

As in pediatric BD, comorbidity is com­mon in ADHD, with uncomplicated ADHD being the exception rather than the rule. Recent studies have suggested that approx­imately two-thirds of children who have a diagnosis of ADHD have ≥1 comorbid diag­noses.¹⁵ Common comorbidities are similar to those seen in BD, including ODD, CD, anxiety disorders, depression, and learning disability. Several tools and resources are available to help clinicians navigate these issues within their practices.

Family history. Genetics appear to play a large role in ADHD, with twin studies suggesting inheritance of approximately 76%.18 Environmental factors contribute, either in the development of ADHD or in the exacerbation of an underlying familial predisposition. Interestingly, in children with BD, family history often is significant for several family members who have both ADHD and BD. However, in children with ADHD only, family history often reflects an absence of family members with BD.19 Although not diagnostic, this pattern can be helpful when considering a diagnosis of BD vs ADHD.

Clinical picture. ADHD often is recog­nized in childhood; DSM-5 criteria spec­ify that symptoms be present before age 12 and persist for at least 6 months. This characterization of the timing of symp­toms helps exclude behavioral disruptions related to external factors such as trauma (eg, death of a caregiver) or abuse. It also is important to note that symptoms might be present earlier but not come to attention clinically until a later age, perhaps because of increasing demands placed on the child by school, peer groups, and extracurricu­lar activities. To make an ADHD diag­nosis, symptoms must be present in >1 setting and interfere with functioning or development.

Core symptoms of ADHD include inat­tention, hyperactivity, and impulsivity that are out of proportion to the child’s developmental level (Table 2).20 When considering diagnosis of ADHD, 6 of 9 symptoms for inattention and/or hyperactivity-impulsivity must be present at a clinically significant level.

Three different ADHD presentations are recognized: combined, inattentive, and hyperactive impulsive. Children with predominant impulsive and hyperactive behaviors generally come to clinical atten­tion at a younger age; inattentive symptoms often take longer to identify.

Children with ADHD have been noted to have lower tolerance for frustration, which might make anger outbursts and aggressive behavior more likely. Anger and aggression in ADHD often stem from impulsivity, rather than irritable mood seen with BD.18 Issues related to self-esteem, depression, substance use, and CD can contribute to symptoms of irrita­bility, anger, and aggression that can occur in children with ADHD. Although these symptoms can overlap with those seen in children with BD, other core symptoms of ADHD will not be present.

ODD is one of the most common comor­bidities among children with ADHD, and the combination of ODD and ADHD may be confused with BD. Children with ODD often are noted to exhibit a pattern of negative and defiant behavior that is out of proportion to what is seen in their peers and for their age and develop­mental level (Table 3).²⁰ When considering an ODD diagnosis, 4 out of 8 symptoms must be present at a clinically significant level.

The following case highlights the poten­tial similarities between ADHD/ODD and BD, with tips on how to distinguish them.

CASE REPORT

Angry and destructiveSam, age 7, has been given a diagnosis of ADHD, but his parents think that he isn’t improving with methylphenidate treatment. They are concerned that he has anger issues like his uncle, who has “bipolar disorder.”

Sam’s parents find that he gets frustrated easily and note that he has frequent short “meltdowns” and “mood swings.” During these episodes he yells, is aggressive towards others, and can be destructive. They are concerned because Sam will become angry quickly, then act as if nothing happened after the meltdown has blown over. Sam’s parents feel that he doesn’t listen to them and often argues when they make a request. His parents note that when they push harder, Sam digs in his heels, which can trigger his meltdowns.

Despite clearly disobeying his parents, Sam often says that things aren’t his fault and blames his parents or siblings instead. Sam seems to disagree with people often. His mother reports “if I say the water looks blue, he’ll say it’s green.” Often, Sam seems to argue or pester others to get a rise out of them. This is causing problems for Sam with his siblings and peers, and significant stress for his parents. Family history suggests that Sam’s uncle may have ADHD with CD or a substance use disorder, rather than true BD. Other than Sam’s uncle, there is no family his­tory for BD.

Sam’s parents say that extended release methylphenidate, 20 mg/d, has helped with hyperactivity, but they are concerned that other symptoms have not improved. Aside from the symptoms listed above, Sam is described as a happy child. There is no his­tory of trauma, and no symptoms of anxiety are noted. Sam sometimes gets “down” when things don’t go his way, but this lasts only for a few hours. Sam has a history of delayed sleep onset, which responded well to melato­nin. No other symptoms that suggest mania are described.

You complete the pediatric bipolar nomo­gram (Figure 3)^6,7 and Sam’s parents com­plete a Vanderbilt ADHD Diagnostic Parent Rating Scale. At first, Sam seems to have sev­eral factors that might indicate BD: aggres­sive behavior, mood swings, sleep problems, and, possibly, a family history of BD.

However, a careful history provides several clues that Sam has a comorbid diagnosis of ODD. Sam is exhibiting the classic pattern of negativist behavior seen in children with ODD. In contrast to the episodic pattern of BD, these symptoms are prevalent and per­sistent, and manifest as an overall pattern of functioning. Impulsivity seen in children with ADHD can complicate the picture, but again appears as a consistent pattern rather than bouts of irritability. Sam’s core symptoms of ADHD (hyperactivity) improved with methyl­phenidate, but the underlying symptoms of ODD persisted.

Sleep problems are common in chil­dren who have ADHD and BD, but Sam’s delayed sleep onset responded to melato­nin, whereas the insomnia seen in BD often is refractory to lower-intensity interven­tions, such as melatonin. Taking a careful family history led you to believe that BD in the family is unlikely. Although this type of detail may not always be available, it can be helpful to ask about mental health symptoms that seem to “run in the family.”

Bottom Line

Distinguishing the child who has bipolar disorder from one who has attention-deficit/hyperactivity disorder can be challenging. A careful history helps ensure that you are on the path toward understanding the diagnostic possibilities. Tools such as the Vanderbilt Rating Scale can further clarify possible diagnoses, and the nomogram approach can provide even more predictive information when considering a diagnosis of bipolar disorder.

Related Resources
• Children and Adults with Attention Deficit/Hyperactivity Disorder (CHADD). www.chadd.org.
• American Academy of Child and Adolescent Psychiatry. Facts for Families. www.aacap.org/cs/root/facts_for_families/ facts_for_families.
• Froehlich TE, Delgado SV, Anixt JS. Expanding medica­tion options for pediatric ADHD. Current Psychiatry. 2013;(12)12:20-29.
• Passarotti AM, Pavuluri MN. Brain functional domains in­form therapeutic interventions in attention-deficit/hyper­activity disorder and pediatric bipolar disorder. Expert Rev Neurother. 2011;11(6):897-914.

Drug Brand Names
Methylphenidate • Ritalin,  Methylin, Metadate CD, Metadate ER, Methylin ER, Ritalin LA, Ritalin SR, Concerta, Quillivant XR, Daytrana

Risperidone • Risperdal

Differentiating the irritable, oppositional child with attention-deficit/hyperactivity disorder (ADHD) from the child with bipolar disorder (BD) often is difficult. To make matters more complicated, 50% to 70% of patients with BD have comorbid ADHD.^1,2 Accordingly, clinicians are often faced with the moody, irritable, dis­ruptive child whose parents want to know if he (she) is “bipolar” to try to deal with oppositional and mood behaviors.

In this article, we present an approach that will help you distinguish these 2 disorders from each other.

Precision medicineThere is a lack of evidence-based methods for diagnosing psychiat­ric disorders in children and adolescents. DSM-5 provides clinicians with diagnostic checklists that rely on the clinician’s judgment and training in evaluating a patient.³ In The innovator’s prescription: a dis­ruptive solution for health care, Christensen et al⁴ describe how medi­cine is moving from “intuitive medicine” to empirical medicine and toward “precision medicine.” Intuitive medicine depends on the clini­cian’s expertise, training, and exposure to different disorders, which is the traditional clinical model that predominates in child psychiatry. Empirical medicine relies on laboratory results, scans, scales, and other standardized tools.

Precision medicine occurs when a disorder can be precisely diag­nosed and its cause understood, and when it can be treated with effec­tive, evidence-based therapies. An example of this movement toward precision is Timothy syndrome (TS), a rare autosomal dominant disorder characterized by physical malformations, cardiac arrhyth­mias and structural heart defects, webbing of fingers and toes, and autism spectrum disorder. In the past, a child with TS would have been given a diagnosis of intellectual disability, or a specialist in developmental disorders might recognize the pattern of TS. It is now known that TS is caused by muta­tions in CACNA1C, the gene encoding the calcium channel Ca_v1.2α subunit, allowing precise diagnosis by genotyping.⁵

Although there are several tools that help clinicians assess symptoms of ADHD and BD, including rating scales such the Vanderbilt ADHD Diagnostic Rating Scale and Young Mania Rating Scale, none of these scales are diagnostic. Youngstrom et al^6,7 have developed an evidence-based strategy to diagnose pediatric BD. This method uses a nomogram that takes into account the base rate of BD in a clinical set­ting and family history of BD.

We will describe and contrast the epi­demiologic and clinical characteristics of pediatric BD from ADHD and use the Youngstrom nomogram to better define these patients. Although still far from pre­cision medicine, the type of approach rep­resents an ongoing effort in mental health care to increase diagnostic accuracy and improve treatment outcomes.

Pediatric bipolar disorder
Prevalence of pediatric BD is 1.8% (95% CI, 1.1% to 3.0%),⁸ which does not include sub-threshold cases of BD. ADHD and oppo­sitional defiant disorder (ODD) are 8 to 10 times more prevalent. For the purposes of the nomogram, the “base rate” is the rate at which a disorder occurs in different clinical settings. In general outpatient clinics, BD might occur 6% to 8% of the time, whereas in a county-run child psychiatry inpatient facility the rate is 11%.⁶ A reasonable rate in an outpatient pediatric setting is 6%.

Family history. In the Bipolar Offspring Study,9 the rate of BD in children of par­ents with BD was 13 times greater than that of controls, and the rate of anxiety and behavior disorders was approximately twice that of children of parents without BD (Table 1).⁹ This study evaluated 388 children of 233 parents with BD and 251 children of 143 demographically matched controls.

Elevated or expansive mood. The child might have a mood that is inappropriately giddy, silly, elated, or euphoric. Often this mood will be present without reason and last for several hours. It may be distin­guished from a transient cheerful mood by the intensity and duration of the episode. The child with BD may have little to no insight about the inappropriate nature of their elevated mood, when present. 

Irritable mood. The child might become markedly belligerent or irritated with intense outbursts of anger, 2 to 3 times a day for several hours. An adolescent might appear extremely oppositional, belliger­ent, or hostile with parents and others. 

Grandiosity or inflated self-esteem can be confused with brief childhood fanta­sies of increased capability. Typically, true grandiosity can manifest as assertion of great competency in all areas of life, which usually cannot be altered by contrary exter­nal evidence. Occasionally, this is bizarre and includes delusions of “super powers.” The child in a manic episode will not only assert that she can fly, but will jump off the garage roof to prove it. 

Decreased need for sleep. The child may only require 4 to 5 hours of sleep a night during a manic episode without feeling fatigued or showing evidence of tiredness. Consider substance use in this differential diagnosis, especially in adolescents.

Increased talkativeness. Lack of inhibi­tion to social norms may lead pediatric BD patients to blurt out answers during class or repeatedly be disciplined for talking to peers in class. Speech typically is rapid and pressured to the point where it might be continuous and seems to jump between loosely related subjects.

Flight of ideas or racing thoughts. The child or adolescent might report a subjec­tive feeling that his thoughts are moving so rapidly that his speech cannot keep up. Often this is differentiated from rapid speech by the degree of rapidity the patient expresses loosely related topics that might seem completely unrelated to the listener.

Distractibility, short attention span. During a manic episode, the child or ado­lescent might report that it is impossible to pay attention to class or other outside events because of rapidly changing focus of their thoughts. This symptom must be care­fully distinguished from the distractibility and inattention of ADHD, which typically is a more fixed and long-standing pattern rather than a brief episodic phenomenon in a manic or hypomanic episode.

Increase in goal-directed activity. During a mild manic episode, the child or adoles­cent may be capable of accomplishing a great deal of work. However, episodes that are more severe manifest as an individual starting numerous ambitious projects that she later is unable to complete.

Excessive risk-taking activities. The child or adolescent might become involved in forbidden, pleasurable activities that have a high risk of adverse consequences. This can manifest as hypersexual behavior, fre­quent fighting, increased recklessness, use of drugs and alcohol, shopping sprees, and reckless driving.

There are few studies comparing patients with comorbid BD and ADHD with patients with only ADHD. Geller et al¹¹ compared 60 children with BD and ADHD (mean age, 10) to age- and sex-matched patients with ADHD and no mood disorder. Compared with children who had ADHD, those with BD exhib­ited significantly greater elevated mood, grandiosity, flight and/or racing of ideas, decreased need for sleep, and hypersexual­ity (Figure 1,¹¹). Features common to both groups—and therefore not useful in differentiating the disorders—included irritability, hyperactivity, accelerated speech, and distractibility.
 

CASE REPORTIrritable and disruptiveBill, age 12, has been brought to see you by his mother because she is concerned about escalating behavior problems at home and school in the past several months. The school principal has called her about his obnoxious behavior with teachers and about other par­ents’ complaints that he has made unwanted sexual advances to girls who sit next to him in class.

Bill, who is in the 7th grade, is on the verge of being suspended for his inappropriate and disruptive behavior. His parents report that he is irritable around them and stays up all night, messaging his friends on the Internet from his iPad in his bedroom. They attribute his inappro­priate sexual behavior to puberty and possibly to the Web sites he views.

Bill’s mother is concerned about his:
   • increasing behavior problems during the last several months at home and school
   • intensifying irritability and depressive symptoms
   • staying up all night on the Internet, phoning friends, and doing projects
   • frequent unprovoked, outbursts of rage occurring with increasing frequency and intensity (almost daily)
   • moderate grandiosity, including telling the soccer coach and teachers how to do their jobs
   • inappropriate sexual behavior, including kissing and touching female classmates.

During your history, you learn that Bill has been a bright and artistic child, with good academic performance. His peer relation­ships have been satisfactory, but not excel­lent—he tends to be “bossy” with his peers. He is medically healthy and not taking any medications. As part of your history, you also talk with Bill and his family about exposure to trauma or significant stressors, which they deny. You learn that Bill’s father was diag­nosed with BD I at age 32.

Completing the nomogram developed by Youngstrom et al^6,7 using these variables (see this article at CurrentPsychiatry.com for Figure 2)^6,7 gives Bill a post-test probability of approximately 42%. The threshold for moving ahead with assessment and possible treat­ment, the “test-treatment threshold,” depends on your clinical setting.^12,13 Our clinical expe­rience is that, when the post-test probability exceeds 30%, further assessment for BD is warranted.

The next strategy is to look at Bill’s scores on externalizing behaviors using an instru­ment such as the Vanderbilt ADHD Diagnostic Parent Rating Scale. Few pediatric patients with BD will score low on externalizing behaviors.14 Bill scores in the clinically signifi­cant range for hyperactivity/impulsivity and positive on the screeners for ODD, conduct disorder (CD), and anxiety/depression.

You decide that Bill is at high risk of pedi­atric BD; he has a post-test probability of approximately 45%, and many externalizing behaviors on the Vanderbilt. You give Bill a diagnosis of BD I and ADHD and prescribe ris­peridone, 0.5 mg/d, which results in signifi­cant improvement in mood swings and other manic behaviors.

ADHD
Epidemiology. ADHD is one of the most common neurodevelopmental disorders in childhood, with prevalence estimates of 8% of U.S. children.^15,16 Overall, boys are more likely to be assigned a diagnosis of ADHD than girls.¹⁵ Although ADHD often is diagnosed in early childhood, research is working to clarify the lifetime preva­lence of ADHD into late adolescence and adulthood. Current estimates suggest that ADHD persists into adulthood in close to two-thirds of patients.¹⁷ However, the symptom presentation can change during adolescence and adulthood, with less overt hyperactivity and symptoms of impulsivity transitioning to risky behaviors involving trouble with the law, substance use, and sexual promiscuity.¹⁷

As in pediatric BD, comorbidity is com­mon in ADHD, with uncomplicated ADHD being the exception rather than the rule. Recent studies have suggested that approx­imately two-thirds of children who have a diagnosis of ADHD have ≥1 comorbid diag­noses.¹⁵ Common comorbidities are similar to those seen in BD, including ODD, CD, anxiety disorders, depression, and learning disability. Several tools and resources are available to help clinicians navigate these issues within their practices.

Family history. Genetics appear to play a large role in ADHD, with twin studies suggesting inheritance of approximately 76%.18 Environmental factors contribute, either in the development of ADHD or in the exacerbation of an underlying familial predisposition. Interestingly, in children with BD, family history often is significant for several family members who have both ADHD and BD. However, in children with ADHD only, family history often reflects an absence of family members with BD.19 Although not diagnostic, this pattern can be helpful when considering a diagnosis of BD vs ADHD.

Clinical picture. ADHD often is recog­nized in childhood; DSM-5 criteria spec­ify that symptoms be present before age 12 and persist for at least 6 months. This characterization of the timing of symp­toms helps exclude behavioral disruptions related to external factors such as trauma (eg, death of a caregiver) or abuse. It also is important to note that symptoms might be present earlier but not come to attention clinically until a later age, perhaps because of increasing demands placed on the child by school, peer groups, and extracurricu­lar activities. To make an ADHD diag­nosis, symptoms must be present in >1 setting and interfere with functioning or development.

Core symptoms of ADHD include inat­tention, hyperactivity, and impulsivity that are out of proportion to the child’s developmental level (Table 2).20 When considering diagnosis of ADHD, 6 of 9 symptoms for inattention and/or hyperactivity-impulsivity must be present at a clinically significant level.

Three different ADHD presentations are recognized: combined, inattentive, and hyperactive impulsive. Children with predominant impulsive and hyperactive behaviors generally come to clinical atten­tion at a younger age; inattentive symptoms often take longer to identify.

Children with ADHD have been noted to have lower tolerance for frustration, which might make anger outbursts and aggressive behavior more likely. Anger and aggression in ADHD often stem from impulsivity, rather than irritable mood seen with BD.18 Issues related to self-esteem, depression, substance use, and CD can contribute to symptoms of irrita­bility, anger, and aggression that can occur in children with ADHD. Although these symptoms can overlap with those seen in children with BD, other core symptoms of ADHD will not be present.

ODD is one of the most common comor­bidities among children with ADHD, and the combination of ODD and ADHD may be confused with BD. Children with ODD often are noted to exhibit a pattern of negative and defiant behavior that is out of proportion to what is seen in their peers and for their age and develop­mental level (Table 3).²⁰ When considering an ODD diagnosis, 4 out of 8 symptoms must be present at a clinically significant level.

The following case highlights the poten­tial similarities between ADHD/ODD and BD, with tips on how to distinguish them.

CASE REPORT

Angry and destructiveSam, age 7, has been given a diagnosis of ADHD, but his parents think that he isn’t improving with methylphenidate treatment. They are concerned that he has anger issues like his uncle, who has “bipolar disorder.”

Sam’s parents find that he gets frustrated easily and note that he has frequent short “meltdowns” and “mood swings.” During these episodes he yells, is aggressive towards others, and can be destructive. They are concerned because Sam will become angry quickly, then act as if nothing happened after the meltdown has blown over. Sam’s parents feel that he doesn’t listen to them and often argues when they make a request. His parents note that when they push harder, Sam digs in his heels, which can trigger his meltdowns.

Despite clearly disobeying his parents, Sam often says that things aren’t his fault and blames his parents or siblings instead. Sam seems to disagree with people often. His mother reports “if I say the water looks blue, he’ll say it’s green.” Often, Sam seems to argue or pester others to get a rise out of them. This is causing problems for Sam with his siblings and peers, and significant stress for his parents. Family history suggests that Sam’s uncle may have ADHD with CD or a substance use disorder, rather than true BD. Other than Sam’s uncle, there is no family his­tory for BD.

Sam’s parents say that extended release methylphenidate, 20 mg/d, has helped with hyperactivity, but they are concerned that other symptoms have not improved. Aside from the symptoms listed above, Sam is described as a happy child. There is no his­tory of trauma, and no symptoms of anxiety are noted. Sam sometimes gets “down” when things don’t go his way, but this lasts only for a few hours. Sam has a history of delayed sleep onset, which responded well to melato­nin. No other symptoms that suggest mania are described.

You complete the pediatric bipolar nomo­gram (Figure 3)^6,7 and Sam’s parents com­plete a Vanderbilt ADHD Diagnostic Parent Rating Scale. At first, Sam seems to have sev­eral factors that might indicate BD: aggres­sive behavior, mood swings, sleep problems, and, possibly, a family history of BD.

However, a careful history provides several clues that Sam has a comorbid diagnosis of ODD. Sam is exhibiting the classic pattern of negativist behavior seen in children with ODD. In contrast to the episodic pattern of BD, these symptoms are prevalent and per­sistent, and manifest as an overall pattern of functioning. Impulsivity seen in children with ADHD can complicate the picture, but again appears as a consistent pattern rather than bouts of irritability. Sam’s core symptoms of ADHD (hyperactivity) improved with methyl­phenidate, but the underlying symptoms of ODD persisted.

Sleep problems are common in chil­dren who have ADHD and BD, but Sam’s delayed sleep onset responded to melato­nin, whereas the insomnia seen in BD often is refractory to lower-intensity interven­tions, such as melatonin. Taking a careful family history led you to believe that BD in the family is unlikely. Although this type of detail may not always be available, it can be helpful to ask about mental health symptoms that seem to “run in the family.”

Bottom Line

Distinguishing the child who has bipolar disorder from one who has attention-deficit/hyperactivity disorder can be challenging. A careful history helps ensure that you are on the path toward understanding the diagnostic possibilities. Tools such as the Vanderbilt Rating Scale can further clarify possible diagnoses, and the nomogram approach can provide even more predictive information when considering a diagnosis of bipolar disorder.

Related Resources
• Children and Adults with Attention Deficit/Hyperactivity Disorder (CHADD). www.chadd.org.
• American Academy of Child and Adolescent Psychiatry. Facts for Families. www.aacap.org/cs/root/facts_for_families/ facts_for_families.
• Froehlich TE, Delgado SV, Anixt JS. Expanding medica­tion options for pediatric ADHD. Current Psychiatry. 2013;(12)12:20-29.
• Passarotti AM, Pavuluri MN. Brain functional domains in­form therapeutic interventions in attention-deficit/hyper­activity disorder and pediatric bipolar disorder. Expert Rev Neurother. 2011;11(6):897-914.

Drug Brand Names
Methylphenidate • Ritalin,  Methylin, Metadate CD, Metadate ER, Methylin ER, Ritalin LA, Ritalin SR, Concerta, Quillivant XR, Daytrana

Risperidone • Risperdal

The deadline has been extended to October 21 to submit letters of intent and abstracts for National Organization for Rare Disorders (NORD) research grants for studies related to the following rare diseases:

• Alveolar capillary dysplasia with misalignment of the pulmonary veins (ACD/MPV)
• Appendix cancer and pseudomyxoma peritonei (PMP)
• Autoimmune polyglandular syndrome type 1 (APS Type 1)
• Homocystinuria due to cystathionine beta-synthase deficiency
• Malonic aciduria
• Stiff person syndrome

The NORD Research Grant Program encourages meritorious scientific and clinical research toward new diagnostics, treatments, and/or cures for rare diseases. NORD’s program provides seed grants to clinicians and academic scientists for translational or clinical studies. Data generated in these studies may then be used by researchers to obtain additional funding from government or industry sponsors. Two of NORD’s previous research grants have resulted in FDA-approved orphan products to treat rare diseases. Submissions should be sent to [email protected]. Click here to view each Request for Proposal in full.

The deadline has been extended to October 21 to submit letters of intent and abstracts for National Organization for Rare Disorders (NORD) research grants for studies related to the following rare diseases:

• Alveolar capillary dysplasia with misalignment of the pulmonary veins (ACD/MPV)
• Appendix cancer and pseudomyxoma peritonei (PMP)
• Autoimmune polyglandular syndrome type 1 (APS Type 1)
• Homocystinuria due to cystathionine beta-synthase deficiency
• Malonic aciduria
• Stiff person syndrome

The NORD Research Grant Program encourages meritorious scientific and clinical research toward new diagnostics, treatments, and/or cures for rare diseases. NORD’s program provides seed grants to clinicians and academic scientists for translational or clinical studies. Data generated in these studies may then be used by researchers to obtain additional funding from government or industry sponsors. Two of NORD’s previous research grants have resulted in FDA-approved orphan products to treat rare diseases. Submissions should be sent to [email protected]. Click here to view each Request for Proposal in full.

The deadline has been extended to October 21 to submit letters of intent and abstracts for National Organization for Rare Disorders (NORD) research grants for studies related to the following rare diseases:

• Alveolar capillary dysplasia with misalignment of the pulmonary veins (ACD/MPV)
• Appendix cancer and pseudomyxoma peritonei (PMP)
• Autoimmune polyglandular syndrome type 1 (APS Type 1)
• Homocystinuria due to cystathionine beta-synthase deficiency
• Malonic aciduria
• Stiff person syndrome

The NORD Research Grant Program encourages meritorious scientific and clinical research toward new diagnostics, treatments, and/or cures for rare diseases. NORD’s program provides seed grants to clinicians and academic scientists for translational or clinical studies. Data generated in these studies may then be used by researchers to obtain additional funding from government or industry sponsors. Two of NORD’s previous research grants have resulted in FDA-approved orphan products to treat rare diseases. Submissions should be sent to [email protected]. Click here to view each Request for Proposal in full.

The average American consumes about 3400 mg/d of sodium, which is more than double the 1500 mg recommended by the American Heart Association.¹ Excess sodium added to foods during commercial processing and preparation represents the main source of sodium intake in American diets.² Nevertheless, adding salt at the table is still very common, and people who add salt at the table have 1.5 g higher salt intakes than those who do not add salt.³ And as we know, high sodium intake has been associated with elevated blood pressure and an increased rate of cardiovascular disease.⁴

I have designed a self-produced “Salt Awareness—Limit Today” (SALT) label (FIGURE). This label is attached to the cap of a salt shaker in such a way that less salt flows through the openings of the cap. Moreover, the label serves as a reminder to limit salt intake in general. The feedback I have received from my patients has been extremely positive; they report increased awareness and decreased sodium intake. I mention it here so that others may benefit.

Zvi Weizman, MD
Beer-Sheva, Israel

The average American consumes about 3400 mg/d of sodium, which is more than double the 1500 mg recommended by the American Heart Association.¹ Excess sodium added to foods during commercial processing and preparation represents the main source of sodium intake in American diets.² Nevertheless, adding salt at the table is still very common, and people who add salt at the table have 1.5 g higher salt intakes than those who do not add salt.³ And as we know, high sodium intake has been associated with elevated blood pressure and an increased rate of cardiovascular disease.⁴

I have designed a self-produced “Salt Awareness—Limit Today” (SALT) label (FIGURE). This label is attached to the cap of a salt shaker in such a way that less salt flows through the openings of the cap. Moreover, the label serves as a reminder to limit salt intake in general. The feedback I have received from my patients has been extremely positive; they report increased awareness and decreased sodium intake. I mention it here so that others may benefit.

Zvi Weizman, MD
Beer-Sheva, Israel

The average American consumes about 3400 mg/d of sodium, which is more than double the 1500 mg recommended by the American Heart Association.¹ Excess sodium added to foods during commercial processing and preparation represents the main source of sodium intake in American diets.² Nevertheless, adding salt at the table is still very common, and people who add salt at the table have 1.5 g higher salt intakes than those who do not add salt.³ And as we know, high sodium intake has been associated with elevated blood pressure and an increased rate of cardiovascular disease.⁴

I have designed a self-produced “Salt Awareness—Limit Today” (SALT) label (FIGURE). This label is attached to the cap of a salt shaker in such a way that less salt flows through the openings of the cap. Moreover, the label serves as a reminder to limit salt intake in general. The feedback I have received from my patients has been extremely positive; they report increased awareness and decreased sodium intake. I mention it here so that others may benefit.

Zvi Weizman, MD
Beer-Sheva, Israel

In his August editorial, Dr. Hickner noted that an article in the issue prompted him to “wonder whether ultrasound might become the stethoscope of the future” (J Fam Pract. 2016;65:516). To that I say that we need to avoid conflating the stethoscope with point-of-care ultrasound (POCUS).

It is well documented that auscultation skills rapidly deteriorate (specifically in the cardiology realm) in clinical practice.¹ This may occur because many physicians already think ultrasound can replace actually listening to their patients’ hearts. The motto has become, “I’ll just order an echo.”

POCUS is an imaging modality. Period. It can be used to auscultate, but Doppler ultrasound is not as precise as the stethoscope when used by a practiced listener for identifying the source and subtle characteristics of murmurs.² The stethoscope remains an outstanding, inexpensive, and convenient screening tool and its use needs to be emphasized.

I strongly believe in training all medical students in POCUS—but as a complementary and adjunctive tool—not as something to replace a perfectly functional piece of equipment used around the world to provide good care.

Todd Fredricks, DO
Athens, Ohio

In his August editorial, Dr. Hickner noted that an article in the issue prompted him to “wonder whether ultrasound might become the stethoscope of the future” (J Fam Pract. 2016;65:516). To that I say that we need to avoid conflating the stethoscope with point-of-care ultrasound (POCUS).

It is well documented that auscultation skills rapidly deteriorate (specifically in the cardiology realm) in clinical practice.¹ This may occur because many physicians already think ultrasound can replace actually listening to their patients’ hearts. The motto has become, “I’ll just order an echo.”

POCUS is an imaging modality. Period. It can be used to auscultate, but Doppler ultrasound is not as precise as the stethoscope when used by a practiced listener for identifying the source and subtle characteristics of murmurs.² The stethoscope remains an outstanding, inexpensive, and convenient screening tool and its use needs to be emphasized.

I strongly believe in training all medical students in POCUS—but as a complementary and adjunctive tool—not as something to replace a perfectly functional piece of equipment used around the world to provide good care.

Todd Fredricks, DO
Athens, Ohio

In his August editorial, Dr. Hickner noted that an article in the issue prompted him to “wonder whether ultrasound might become the stethoscope of the future” (J Fam Pract. 2016;65:516). To that I say that we need to avoid conflating the stethoscope with point-of-care ultrasound (POCUS).

It is well documented that auscultation skills rapidly deteriorate (specifically in the cardiology realm) in clinical practice.¹ This may occur because many physicians already think ultrasound can replace actually listening to their patients’ hearts. The motto has become, “I’ll just order an echo.”

POCUS is an imaging modality. Period. It can be used to auscultate, but Doppler ultrasound is not as precise as the stethoscope when used by a practiced listener for identifying the source and subtle characteristics of murmurs.² The stethoscope remains an outstanding, inexpensive, and convenient screening tool and its use needs to be emphasized.

I strongly believe in training all medical students in POCUS—but as a complementary and adjunctive tool—not as something to replace a perfectly functional piece of equipment used around the world to provide good care.

Todd Fredricks, DO
Athens, Ohio

The article, “Diabetes update: Your guide to the latest ADA standards,” by Shubrook, et al (J Fam Pract. 2016;65:310-318) is a precise review of current recommendations for diabetes. We would like to draw attention, however, to comorbid diabetes and mental illness.

Diabetes and serious mental illness often coincide, making the treatment of both conditions difficult and leading to higher rates of complications.¹

The American Diabetes Association (ADA)’s “Standards of Medical Care in Diabetes” recognizes that hemoglobin A1C targets for patients should be individualized.² We consider it important to discuss challenges and limitations with each patient.

For example, a more lenient A1C goal may be appropriate when:

• the assessment of the patient shows that he or she is struggling with active symptoms of mental illness
• new medications with undesirable metabolic effects are prescribed or titrated
• social support is poor
• patients have limited confidence in their ability to accomplish tasks and goals
• patients have cognitive limitations
• patients abuse substances.

We suggest that when factors are favorable (eg, younger patient, well-controlled serious mental illness, adequate support, good cognitive skills, no hazardous use of substances, good level of confidence in the ability to control diabetes), the A1C target can be set lower. When the factors are less favorable (eg, older patient, poorly controlled mental illness, abusing substances, cognitive impairment), the target should be set higher and incrementally reduced as care engagement, circumstances, and symptom control improve.

There is a need for further research to investigate the factors that can impact diabetes self-management in patients with comorbid mental illness.

Corinna Falck-Ytter, MD
Stephanie W. Kanuch, MEd
Richard McCormick, PhD
Michael Purdum, PhD
Neal V. Dawson, MD
Shari D. Bolen, MD, MPH
Martha Sajatovic, MD
Cleveland, Ohio

The article, “Diabetes update: Your guide to the latest ADA standards,” by Shubrook, et al (J Fam Pract. 2016;65:310-318) is a precise review of current recommendations for diabetes. We would like to draw attention, however, to comorbid diabetes and mental illness.

Diabetes and serious mental illness often coincide, making the treatment of both conditions difficult and leading to higher rates of complications.¹

The American Diabetes Association (ADA)’s “Standards of Medical Care in Diabetes” recognizes that hemoglobin A1C targets for patients should be individualized.² We consider it important to discuss challenges and limitations with each patient.

For example, a more lenient A1C goal may be appropriate when:

• the assessment of the patient shows that he or she is struggling with active symptoms of mental illness
• new medications with undesirable metabolic effects are prescribed or titrated
• social support is poor
• patients have limited confidence in their ability to accomplish tasks and goals
• patients have cognitive limitations
• patients abuse substances.

We suggest that when factors are favorable (eg, younger patient, well-controlled serious mental illness, adequate support, good cognitive skills, no hazardous use of substances, good level of confidence in the ability to control diabetes), the A1C target can be set lower. When the factors are less favorable (eg, older patient, poorly controlled mental illness, abusing substances, cognitive impairment), the target should be set higher and incrementally reduced as care engagement, circumstances, and symptom control improve.

There is a need for further research to investigate the factors that can impact diabetes self-management in patients with comorbid mental illness.

Corinna Falck-Ytter, MD
Stephanie W. Kanuch, MEd
Richard McCormick, PhD
Michael Purdum, PhD
Neal V. Dawson, MD
Shari D. Bolen, MD, MPH
Martha Sajatovic, MD
Cleveland, Ohio

The article, “Diabetes update: Your guide to the latest ADA standards,” by Shubrook, et al (J Fam Pract. 2016;65:310-318) is a precise review of current recommendations for diabetes. We would like to draw attention, however, to comorbid diabetes and mental illness.

Diabetes and serious mental illness often coincide, making the treatment of both conditions difficult and leading to higher rates of complications.¹

The American Diabetes Association (ADA)’s “Standards of Medical Care in Diabetes” recognizes that hemoglobin A1C targets for patients should be individualized.² We consider it important to discuss challenges and limitations with each patient.

For example, a more lenient A1C goal may be appropriate when:

• the assessment of the patient shows that he or she is struggling with active symptoms of mental illness
• new medications with undesirable metabolic effects are prescribed or titrated
• social support is poor
• patients have limited confidence in their ability to accomplish tasks and goals
• patients have cognitive limitations
• patients abuse substances.

We suggest that when factors are favorable (eg, younger patient, well-controlled serious mental illness, adequate support, good cognitive skills, no hazardous use of substances, good level of confidence in the ability to control diabetes), the A1C target can be set lower. When the factors are less favorable (eg, older patient, poorly controlled mental illness, abusing substances, cognitive impairment), the target should be set higher and incrementally reduced as care engagement, circumstances, and symptom control improve.

There is a need for further research to investigate the factors that can impact diabetes self-management in patients with comorbid mental illness.

Corinna Falck-Ytter, MD
Stephanie W. Kanuch, MEd
Richard McCormick, PhD
Michael Purdum, PhD
Neal V. Dawson, MD
Shari D. Bolen, MD, MPH
Martha Sajatovic, MD
Cleveland, Ohio

An 88-year-old woman presented to our primary care clinic with recurrent right upper quadrant abdominal pain. Her history was negative for nausea, fever, vomiting, chest pain, heartburn, back pain, or changes in bowel movement patterns. There was no association between the pain and her eating patterns. She described the pain as dull, and rated it as a 4 to 5 out of 10. A physical examination was unremarkable except for a minimally tender mass in the right upper quadrant that was detected during palpation of the abdomen. A Murphy’s test was negative. A comprehensive metabolic panel, complete blood count, lipase test, amylase test, abdominal ultrasound, and abdominal x-ray (FIGURE) were ordered.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

 

Diagnosis: Porcelain gallbladder

We diagnosed this patient with porcelain gallbladder based on her history, physical exam, and x-ray, which revealed a well-defined air gas bubble encased in a calcified pouch. (The patient’s lab work was unremarkable and the ultrasound revealed the same findings as seen on the x-ray.)

Porcelain gallbladder is a rare condition.¹ It is characterized by intramural calcifications of the gallbladder wall, which is rarely seen with chronic cholecystitis.²

One theory suggests that porcelain gallbladder is due to the obstruction of cystic ducts, which leads to bile stasis in the gallbladder, followed by the accumulation of calcium carbonate salts.

There are a few theories behind the etiology of porcelain gallbladder. One theory is that gallstones can irritate the gallbladder wall, leading to inflammation and then calcification. Others believe that porcelain gallbladder is due to the obstruction of cystic ducts, which leads to bile stasis in the gallbladder, followed by the accumulation of calcium carbonate salts.³

Patients may present with biliary pain or a firm palpable mass in the right upper quadrant. However, patients are often asymptomatic.⁴

Cancer risk. There is about a 2% to 3% risk of gallbladder cancer in patients with porcelain gallbladder.⁵ The nature of the calcification has been linked to the probability that a patient will develop gallbladder cancer. Specifically, there is a higher probability of gallbladder cancer if discontinuous calcification is noted, or if only some portion of the gallbladder wall has calcified.⁶ About 80% of all gallbladder cancers are adenocarcinomas.⁶

Differential diagnosis includes GERD, cholecystitis

Right upper quadrant pain is associated with acute hepatitis, acute cholecystitis, acute pancreatitis, gastroesophageal reflex disease (GERD), ulcers, and umbilical hernias. In this patient’s case, her history and physical examination made a number of diagnoses less likely, including acute cholecystitis, GERD, ulcers, and an umbilical hernia. In addition, normal values on the patient’s lipase and amylase tests ruled out pancreatitis.

Imaging brought things into focus. The most significant finding in this case was the abdominal x-ray, which showed a well-defined air gas bubble encased in a calcified pouch.

In addition to an x-ray or an ultrasound, a computed tomography scan can confirm the diagnosis of porcelain gallbladder.

For most patients, cholecystectomy is recommended

Treatment and management is based on the pattern of calcification and the patient’s current health status. If there is incomplete calcification, cholecystectomy is warranted. Cholecystectomy may also be warranted when a patient is symptomatic and has complete calcification of the gallbladder. Regardless of the pattern of calcification, imaging surveillance of the patient is necessary. Moreover, cholecystectomy is preferred regardless of the status of the calcification if the patient is a good surgical candidate.⁷

It is important to send the gallbladder for histopathological examination after it is removed to determine the likelihood of malignancy.⁷ If cancer is ruled out, then no further work-up is necessary. If cancer is detected, then further evaluation, including additional surgery, may be necessary.

Our patient was a good surgical candidate, so we recommended cholecystectomy. The patient underwent surgery and the pathology report was negative for cancer.

CORRESPONDENCE
Pradeepa Vimalachandran, MD, MPH, 601 North 30th Street, Suite 6720, Omaha, NE 68131; [email protected].

An 88-year-old woman presented to our primary care clinic with recurrent right upper quadrant abdominal pain. Her history was negative for nausea, fever, vomiting, chest pain, heartburn, back pain, or changes in bowel movement patterns. There was no association between the pain and her eating patterns. She described the pain as dull, and rated it as a 4 to 5 out of 10. A physical examination was unremarkable except for a minimally tender mass in the right upper quadrant that was detected during palpation of the abdomen. A Murphy’s test was negative. A comprehensive metabolic panel, complete blood count, lipase test, amylase test, abdominal ultrasound, and abdominal x-ray (FIGURE) were ordered.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

 

Diagnosis: Porcelain gallbladder

We diagnosed this patient with porcelain gallbladder based on her history, physical exam, and x-ray, which revealed a well-defined air gas bubble encased in a calcified pouch. (The patient’s lab work was unremarkable and the ultrasound revealed the same findings as seen on the x-ray.)

Porcelain gallbladder is a rare condition.¹ It is characterized by intramural calcifications of the gallbladder wall, which is rarely seen with chronic cholecystitis.²

One theory suggests that porcelain gallbladder is due to the obstruction of cystic ducts, which leads to bile stasis in the gallbladder, followed by the accumulation of calcium carbonate salts.

There are a few theories behind the etiology of porcelain gallbladder. One theory is that gallstones can irritate the gallbladder wall, leading to inflammation and then calcification. Others believe that porcelain gallbladder is due to the obstruction of cystic ducts, which leads to bile stasis in the gallbladder, followed by the accumulation of calcium carbonate salts.³

Patients may present with biliary pain or a firm palpable mass in the right upper quadrant. However, patients are often asymptomatic.⁴

Cancer risk. There is about a 2% to 3% risk of gallbladder cancer in patients with porcelain gallbladder.⁵ The nature of the calcification has been linked to the probability that a patient will develop gallbladder cancer. Specifically, there is a higher probability of gallbladder cancer if discontinuous calcification is noted, or if only some portion of the gallbladder wall has calcified.⁶ About 80% of all gallbladder cancers are adenocarcinomas.⁶

Differential diagnosis includes GERD, cholecystitis

Right upper quadrant pain is associated with acute hepatitis, acute cholecystitis, acute pancreatitis, gastroesophageal reflex disease (GERD), ulcers, and umbilical hernias. In this patient’s case, her history and physical examination made a number of diagnoses less likely, including acute cholecystitis, GERD, ulcers, and an umbilical hernia. In addition, normal values on the patient’s lipase and amylase tests ruled out pancreatitis.

Imaging brought things into focus. The most significant finding in this case was the abdominal x-ray, which showed a well-defined air gas bubble encased in a calcified pouch.

In addition to an x-ray or an ultrasound, a computed tomography scan can confirm the diagnosis of porcelain gallbladder.

For most patients, cholecystectomy is recommended

Treatment and management is based on the pattern of calcification and the patient’s current health status. If there is incomplete calcification, cholecystectomy is warranted. Cholecystectomy may also be warranted when a patient is symptomatic and has complete calcification of the gallbladder. Regardless of the pattern of calcification, imaging surveillance of the patient is necessary. Moreover, cholecystectomy is preferred regardless of the status of the calcification if the patient is a good surgical candidate.⁷

It is important to send the gallbladder for histopathological examination after it is removed to determine the likelihood of malignancy.⁷ If cancer is ruled out, then no further work-up is necessary. If cancer is detected, then further evaluation, including additional surgery, may be necessary.

Our patient was a good surgical candidate, so we recommended cholecystectomy. The patient underwent surgery and the pathology report was negative for cancer.

CORRESPONDENCE
Pradeepa Vimalachandran, MD, MPH, 601 North 30th Street, Suite 6720, Omaha, NE 68131; [email protected].

An 88-year-old woman presented to our primary care clinic with recurrent right upper quadrant abdominal pain. Her history was negative for nausea, fever, vomiting, chest pain, heartburn, back pain, or changes in bowel movement patterns. There was no association between the pain and her eating patterns. She described the pain as dull, and rated it as a 4 to 5 out of 10. A physical examination was unremarkable except for a minimally tender mass in the right upper quadrant that was detected during palpation of the abdomen. A Murphy’s test was negative. A comprehensive metabolic panel, complete blood count, lipase test, amylase test, abdominal ultrasound, and abdominal x-ray (FIGURE) were ordered.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

 

Diagnosis: Porcelain gallbladder

We diagnosed this patient with porcelain gallbladder based on her history, physical exam, and x-ray, which revealed a well-defined air gas bubble encased in a calcified pouch. (The patient’s lab work was unremarkable and the ultrasound revealed the same findings as seen on the x-ray.)

Porcelain gallbladder is a rare condition.¹ It is characterized by intramural calcifications of the gallbladder wall, which is rarely seen with chronic cholecystitis.²

One theory suggests that porcelain gallbladder is due to the obstruction of cystic ducts, which leads to bile stasis in the gallbladder, followed by the accumulation of calcium carbonate salts.

There are a few theories behind the etiology of porcelain gallbladder. One theory is that gallstones can irritate the gallbladder wall, leading to inflammation and then calcification. Others believe that porcelain gallbladder is due to the obstruction of cystic ducts, which leads to bile stasis in the gallbladder, followed by the accumulation of calcium carbonate salts.³

Patients may present with biliary pain or a firm palpable mass in the right upper quadrant. However, patients are often asymptomatic.⁴

Cancer risk. There is about a 2% to 3% risk of gallbladder cancer in patients with porcelain gallbladder.⁵ The nature of the calcification has been linked to the probability that a patient will develop gallbladder cancer. Specifically, there is a higher probability of gallbladder cancer if discontinuous calcification is noted, or if only some portion of the gallbladder wall has calcified.⁶ About 80% of all gallbladder cancers are adenocarcinomas.⁶

Differential diagnosis includes GERD, cholecystitis

Right upper quadrant pain is associated with acute hepatitis, acute cholecystitis, acute pancreatitis, gastroesophageal reflex disease (GERD), ulcers, and umbilical hernias. In this patient’s case, her history and physical examination made a number of diagnoses less likely, including acute cholecystitis, GERD, ulcers, and an umbilical hernia. In addition, normal values on the patient’s lipase and amylase tests ruled out pancreatitis.

Imaging brought things into focus. The most significant finding in this case was the abdominal x-ray, which showed a well-defined air gas bubble encased in a calcified pouch.

In addition to an x-ray or an ultrasound, a computed tomography scan can confirm the diagnosis of porcelain gallbladder.

For most patients, cholecystectomy is recommended

Treatment and management is based on the pattern of calcification and the patient’s current health status. If there is incomplete calcification, cholecystectomy is warranted. Cholecystectomy may also be warranted when a patient is symptomatic and has complete calcification of the gallbladder. Regardless of the pattern of calcification, imaging surveillance of the patient is necessary. Moreover, cholecystectomy is preferred regardless of the status of the calcification if the patient is a good surgical candidate.⁷

It is important to send the gallbladder for histopathological examination after it is removed to determine the likelihood of malignancy.⁷ If cancer is ruled out, then no further work-up is necessary. If cancer is detected, then further evaluation, including additional surgery, may be necessary.

Our patient was a good surgical candidate, so we recommended cholecystectomy. The patient underwent surgery and the pathology report was negative for cancer.

CORRESPONDENCE
Pradeepa Vimalachandran, MD, MPH, 601 North 30th Street, Suite 6720, Omaha, NE 68131; [email protected].

Evidence summary

A cross-sectional study found no correlation between knuckle popping and osteoarthritis (OA) of the hand.¹ Investigators recruited 300 consecutive patients (ages 45 years and older, mean age 63 years) and evaluated them for a history of habitual knuckle popping (74 of 300 patients, mean duration 35 years) and hand arthritis or dysfunction. Investigators excluded patients with neuromuscular, inflammatory, or malignant diseases.

Investigators found OA equally in both patients who did and didn’t pop their knuckles (12 of 74 vs 36 of 226, respectively; P nonsignificant); joint swelling was more common in participants with a history of knuckle popping (84% vs 6%; P<.01). Investigators didn’t describe how OA was diagnosed or specify which joints were affected.

Another cross-sectional study also found no correlation between habitual knuckle popping of the metacarpal phalangeal joint and the prevalence of OA in that joint.² Investigators recruited 28 patients (mean age 78.5 years; 23 women and 5 men) from a Jewish home for the aged and asked them whether they had habitually cracked their knuckles during their lifetime. They then performed clinical and radiographic hand examinations (excluding patients with a history of ­traumatic injury, rheumatoid arthritis, gout, chondrocalcinosis, and hemochromatosis).

Knuckle popping didn’t correlate with OA of the metacarpal phalanges (1 of 15 knuckle popping patients vs 5 of 13 patients who didn’t pop their knuckles; P=.06). All 6 patients with radiographic evidence of OA showed involvement at the metacarpal phalangeal and distal interphalangeal joints, whether or not they popped their knuckles.

A case control study found no correlation between OA in the hands and habitual knuckle popping.³ Investigators recruited 215 patients 50 to 89 years old who had received a radiograph of their right hand during the previous 5 years and divided them into cases with OA (135 patients), and controls without OA (80 patients). Patients completed questionnaires assessing the prevalence (20%), frequency (1 to 20 times per day), and duration (26 to 36 years) of knuckle popping.

Patients most commonly popped proximal interphalangeal joints (15.9%) followed by metacarpal phalangeal joints (13.5%), distal interphalangeal joints (6.1%), and first carpal metacarpal joints (2.3%). OA most often affected the distal interphalangeal joint (68.4%), followed by the first carpal metacarpal (57.1%), proximal interphalangeal (54.1%), and metacarpal phalangeal joints (28.6%). Investigators found no difference in the prevalence of knuckle popping between cases and controls (18% in cases vs 23.2% in controls; P=.361).

When investigators evaluated total knuckle popping exposure in “crack years” (number of times per day multiplied by years) in the distal interphalangeal or metacarpal phalangeal joints, they found no significant association between crack years and OA (distal interphalangeal joint, mean 108 crack years; metacarpal phalangeal joint, mean 75 crack years).

50 years of knuckle popping without ill effects

An n-of-1 case control study found similar results.⁴ The researcher, a physician, popped only the knuckles of his left hand, twice a day, for 50 years. He compared his hands at the end of the trial and found no arthritis in either hand and no visible differences.

But knuckle popping does have a downside

A paper described 2 case reports of acute injuries sustained during attempted knuckle popping—a partial tear of the ulnar collateral ligament of the thumb and subluxation of the extensor tendon of the fifth digit.⁵ Both injuries were associated with forceful manipulation of the digits, and both resolved with conservative management within 4 weeks.

Evidence summary

A cross-sectional study found no correlation between knuckle popping and osteoarthritis (OA) of the hand.¹ Investigators recruited 300 consecutive patients (ages 45 years and older, mean age 63 years) and evaluated them for a history of habitual knuckle popping (74 of 300 patients, mean duration 35 years) and hand arthritis or dysfunction. Investigators excluded patients with neuromuscular, inflammatory, or malignant diseases.

Investigators found OA equally in both patients who did and didn’t pop their knuckles (12 of 74 vs 36 of 226, respectively; P nonsignificant); joint swelling was more common in participants with a history of knuckle popping (84% vs 6%; P<.01). Investigators didn’t describe how OA was diagnosed or specify which joints were affected.

Another cross-sectional study also found no correlation between habitual knuckle popping of the metacarpal phalangeal joint and the prevalence of OA in that joint.² Investigators recruited 28 patients (mean age 78.5 years; 23 women and 5 men) from a Jewish home for the aged and asked them whether they had habitually cracked their knuckles during their lifetime. They then performed clinical and radiographic hand examinations (excluding patients with a history of ­traumatic injury, rheumatoid arthritis, gout, chondrocalcinosis, and hemochromatosis).

Knuckle popping didn’t correlate with OA of the metacarpal phalanges (1 of 15 knuckle popping patients vs 5 of 13 patients who didn’t pop their knuckles; P=.06). All 6 patients with radiographic evidence of OA showed involvement at the metacarpal phalangeal and distal interphalangeal joints, whether or not they popped their knuckles.

A case control study found no correlation between OA in the hands and habitual knuckle popping.³ Investigators recruited 215 patients 50 to 89 years old who had received a radiograph of their right hand during the previous 5 years and divided them into cases with OA (135 patients), and controls without OA (80 patients). Patients completed questionnaires assessing the prevalence (20%), frequency (1 to 20 times per day), and duration (26 to 36 years) of knuckle popping.

Patients most commonly popped proximal interphalangeal joints (15.9%) followed by metacarpal phalangeal joints (13.5%), distal interphalangeal joints (6.1%), and first carpal metacarpal joints (2.3%). OA most often affected the distal interphalangeal joint (68.4%), followed by the first carpal metacarpal (57.1%), proximal interphalangeal (54.1%), and metacarpal phalangeal joints (28.6%). Investigators found no difference in the prevalence of knuckle popping between cases and controls (18% in cases vs 23.2% in controls; P=.361).

When investigators evaluated total knuckle popping exposure in “crack years” (number of times per day multiplied by years) in the distal interphalangeal or metacarpal phalangeal joints, they found no significant association between crack years and OA (distal interphalangeal joint, mean 108 crack years; metacarpal phalangeal joint, mean 75 crack years).

50 years of knuckle popping without ill effects

An n-of-1 case control study found similar results.⁴ The researcher, a physician, popped only the knuckles of his left hand, twice a day, for 50 years. He compared his hands at the end of the trial and found no arthritis in either hand and no visible differences.

But knuckle popping does have a downside

A paper described 2 case reports of acute injuries sustained during attempted knuckle popping—a partial tear of the ulnar collateral ligament of the thumb and subluxation of the extensor tendon of the fifth digit.⁵ Both injuries were associated with forceful manipulation of the digits, and both resolved with conservative management within 4 weeks.

Evidence summary

A cross-sectional study found no correlation between knuckle popping and osteoarthritis (OA) of the hand.¹ Investigators recruited 300 consecutive patients (ages 45 years and older, mean age 63 years) and evaluated them for a history of habitual knuckle popping (74 of 300 patients, mean duration 35 years) and hand arthritis or dysfunction. Investigators excluded patients with neuromuscular, inflammatory, or malignant diseases.

Investigators found OA equally in both patients who did and didn’t pop their knuckles (12 of 74 vs 36 of 226, respectively; P nonsignificant); joint swelling was more common in participants with a history of knuckle popping (84% vs 6%; P<.01). Investigators didn’t describe how OA was diagnosed or specify which joints were affected.

Another cross-sectional study also found no correlation between habitual knuckle popping of the metacarpal phalangeal joint and the prevalence of OA in that joint.² Investigators recruited 28 patients (mean age 78.5 years; 23 women and 5 men) from a Jewish home for the aged and asked them whether they had habitually cracked their knuckles during their lifetime. They then performed clinical and radiographic hand examinations (excluding patients with a history of ­traumatic injury, rheumatoid arthritis, gout, chondrocalcinosis, and hemochromatosis).

Knuckle popping didn’t correlate with OA of the metacarpal phalanges (1 of 15 knuckle popping patients vs 5 of 13 patients who didn’t pop their knuckles; P=.06). All 6 patients with radiographic evidence of OA showed involvement at the metacarpal phalangeal and distal interphalangeal joints, whether or not they popped their knuckles.

A case control study found no correlation between OA in the hands and habitual knuckle popping.³ Investigators recruited 215 patients 50 to 89 years old who had received a radiograph of their right hand during the previous 5 years and divided them into cases with OA (135 patients), and controls without OA (80 patients). Patients completed questionnaires assessing the prevalence (20%), frequency (1 to 20 times per day), and duration (26 to 36 years) of knuckle popping.

Patients most commonly popped proximal interphalangeal joints (15.9%) followed by metacarpal phalangeal joints (13.5%), distal interphalangeal joints (6.1%), and first carpal metacarpal joints (2.3%). OA most often affected the distal interphalangeal joint (68.4%), followed by the first carpal metacarpal (57.1%), proximal interphalangeal (54.1%), and metacarpal phalangeal joints (28.6%). Investigators found no difference in the prevalence of knuckle popping between cases and controls (18% in cases vs 23.2% in controls; P=.361).

When investigators evaluated total knuckle popping exposure in “crack years” (number of times per day multiplied by years) in the distal interphalangeal or metacarpal phalangeal joints, they found no significant association between crack years and OA (distal interphalangeal joint, mean 108 crack years; metacarpal phalangeal joint, mean 75 crack years).

50 years of knuckle popping without ill effects

An n-of-1 case control study found similar results.⁴ The researcher, a physician, popped only the knuckles of his left hand, twice a day, for 50 years. He compared his hands at the end of the trial and found no arthritis in either hand and no visible differences.

But knuckle popping does have a downside

A paper described 2 case reports of acute injuries sustained during attempted knuckle popping—a partial tear of the ulnar collateral ligament of the thumb and subluxation of the extensor tendon of the fifth digit.⁵ Both injuries were associated with forceful manipulation of the digits, and both resolved with conservative management within 4 weeks.