Category Archives: Hepatology

CDC: Increase in Acute Hep B in Appalachia

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MMWR 2016; 65: 47-50. Increases in Acute Hepatitis B Virus Infections — Kentucky, Tennessee, and West Virginia, 2006–2013

An excerpt:

  • During 2006–2013, a total of 3,305 cases of acute HBV infection were reported to CDC from Kentucky, Tennessee, and West Virginia. During 2009–2013, incidence of acute HBV infection increased 114% in these three states, but remained stable in the United States overall
  • Among cases in which at least one risk factor was reported, the proportion of persons reporting injection drug use as a risk factor was significantly greater in 2010–2013, compared with 2006–2009 (75% versus 53%; p<0.001)…the increase was statistically significant only among cases occurring in non-urban counties
  • The findings in this report are subject to …limitations. First, NNDSS is a passive surveillance system, and therefore, unreported cases might have been missed. Second, the current case definition for acute HBV infection captures only symptomatic persons and excludes persons with asymptomatic HBV … Third, … certain populations at high risk (e.g., persons who are incarcerated, homeless, and uninsured) with limited access to care could potentially be underrepresented

My take: Increased drug use appears to be driving an increase in acute HBV in Appalachia. “Evidence-based prevention strategies, including increasing hepatitis B vaccination coverage, testing and linkage to care activities, and education campaigns targeting persons who inject drugs are urgently needed.”

Gibbs Gardens, Ball Ground

Gibbs Gardens, Ball Ground

Drug-Induced Liver and Skin Reactions

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A recent study (H Devarbhavi et al. Hepatology 2016; 63: 993-99 & associated editorial 700–2) provide insight into outcomes and causative agents in patients who had both drug-induced liver injury (DILI) along with severe skin reactions.

With regard to the skin reactions, the authors were specifically focused on Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN).  SJS indicates an area of skin detachment of <10% and TEN involves >30%.  SJS/TEN overlap is 10-30%.

The study reviewed a single center DILI registry over 18 years with 748 patients.  There was prospective recruitment during the final 10 years of the study period (1997-2015). 36 (4.8%) had either SJS or TEN (mean age 32 years, 53% females).  9/36 (25%) were <18 years.

Causative agents:

  • Antiepileptics 47%
  • Sulfonamides 18%
  • Nevirapine 16%
  • Multiple agents 61%

Key points:

  • Median duration between drug initiation and onset of rash was 24 days
  • 13/36 (36%) died. 77% of those who died had jaundice.
  • 14/36 (39%) received steroids including 10 survivors and 4 who died.

While a mortality of 36% among those with both DILI and SJS/TEN is high, the discussion notes that the mortality is high even in those without DILI (~18% in ones study).  There were 8/36 in the study with HIV which is associated with a much higher risk of DILI.  There was a lower mortality in the pediatric age group (1 child 11%) and in those with HIV (1 patient 12.5%).

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Walnut Street Bridge

Walnut Street Bridge

Liver Transplant Recipients Are Getting Older

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Data(F Su et. al. Gastroenterol 2016; 150: 441-53) from 2002 thru 2014 indicate that liver transplant recipients are getting older.

The researchers reviewed data from the United Network for Organ Sharing (UNOS), including 60,820 adults who underwent liver transplantation and 122,606 listed for transplantation. Key findings:

  • Mean age of those listed increased from 51.2 to 55.7 years.  This trend was more prominent among those with hepatitis C (50.9 –>57.9).
  • The proportion of listed patients ≥60 years increased from 19% to 41%.
  • There were no differences in 5-year transplant-related survival “benefit”

The topic of survival “benefit” is reviewed in the discussion and the associated editorial (pg 306).  The survival benefit is calculated as the difference between life expectancy with and without liver transplantation. So, even though older transplant recipients have worse post-transplantation survival, this is counterbalance by the increased risk of waitlist mortality.  It is quite likely, however, that with more time (>5 year followup) that the survival benefit for younger patients would be more apparent.  In addition, the idea that the survival benefit could be equivalent could be influenced by selection bias.  Many transplant centers may be more selective when deciding to place older patients (>70 years) on the waitlist.

My take: The steady increase in age in adult liver transplant recipients is a concern due to worse outcomes in older patients.  This trend could be reversed if hepatitis C becomes a less frequent indication for liver transplantation.

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What happens with 98,500 IU/day of Vitamin A

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An interesting case report (LA Beste et al. NEJM 2016; 374: 73-8) reviews the presentation of a previously healthy 54 year old with ascites.  He initially indicated that he was taking 100 IU per day of vitamin A (his current dose), but later on directed questioning admitted that he had averaged 98,500 IU/day for prior 6 months.

The clinical-problem solving case reviews useful pointers about portal hypertension and in particularly noncirrhotic portal hypertension.  Vitamin A is a rare cause of noncirrhotic portal hypertension.

Other causes of noncirrhotic portal hypertension:

  • Prehepatic level: portal vein or splenic vein thrombosis, splanchnic arteriovenous malformation
  • Intrahepatic level: hepatic vasculitis, HIV infection, infiltrative disease, and medications
  • Posthepatic: Budd-Chiari syndrome, IVC obstruction, restrictive cardiac disease.
  • Worldwide, schistosomiasis is the most common reason.
  • When other causes have been excluded, idiopathic noncirrhotic portal hypertension may be diagnosed, “especially in patients with chronic infection, thrombophilia, and immunologic conditions such as SLE.”  In one series of 69 patients, the diagnosis of idiopathic noncirrhotic portal hypertension was delayed for more than a year in 25% of cases and 7% received an erroneous diagnosis of cryptogenic cirrhosis.

Other points:

  • When ascites is due to cirrhosis, other signs of liver disease are typically present, including jaundice and laboratory findings (low albumin, coagulopathy, hyperbilirubinemia) as well as absence of cirrhosis on biopsy.
  • Serum retinol levels poorly reflect total body stores of vitamin A (& was normal in this patient)
  • Vitamin A supplementation in appropriate doses can prevent blindness in areas where food stores are not secure.  But, consuming excessive doses can lead to being a case report.

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Mural, Old town San Juan

Mural, Old town San Juan

Guidelines: Microscopic Colitis & Vascular Diseases of the Liver

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In brief:

AGA Microscopic Colitis Guideline: GC Nguyen et al. Gastroenterol 2016; 150: 242-6. Technical review DS Pardi et al. Gastroenterol 2016; 150: 247-74. Patient guide: pg 275.

EASL Clinical Practice Guidelines: Vascular diseases of the liver. J Hepatology 2016; 64: 179-202.  Topics covered include Budd-Chiari, Portal vein obstruction, Heriditary hemorrhagic telangiectasia, veno-occlusive disease of the liver, management of anticoagulation in liver disease

Predicting a Bad End in Drug-Induced Liver Injury

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A recent study (VL Re et al. Clin Gastroenterol Hepatol 2015; 13: 2360-68) examined a retrospective cohort of 15,353 patients with presumed drug-induced liver injury (DILI) to formulate a more sensitive model for predicting liver failure.

The authors note that Hy’s Law has good specificity but poor sensitivity.  In their population, Hy’s Law had a specificity of 0.92, negative predictive value of 0.99, sensitivity of 0.68, and a positive predictive value of 0.02.

  • Hy’s law (named for Hyman Zimmerman): AST or ALT > 3 ULN and total bilirubin ≥2 ULN indicate serious hepatotoxicity with >10% mortality rate.

By incorporating data from platelet count and total bilirubin, the authors devised a Drug-Induced Liver Toxicity ALF Score which had a high sensitivity of 0.91 but a lower specificity of 0.76.

  • DrILTox ALF Score = -0.00691292*platelet count + 0.19091500*total bilirubin (per mg/dL)
  • Example: platelet count of 145 & total bilirubin of 3.0 yields a valued of -0.4296 which is above cut off of -1.081 indicating an increased risk of ALF.

Thus, low platelet counts and high bilirubins are strong predictors of acute liver failure (ALF) in the setting of DILI.

My take: Overall, the incidence of ALF due to drugs remains fairly low and determining that a specific drug induced liver injury remains problematic.  This study shows that ALF can occur in those who do not meet Hy’s Law criteria and that more sensitive predictors are needed.

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Burden of GI Diseases in U.S.

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A useful article (AF Peery et al. Gastroenterol 2015; 149: 1731-41) provides data on the huge impact that GI & Liver diseases have.

Here are some key findings:

Leading GI symptoms (Ambulatory visits) in 2010 (Table 1):

  • Abdominal pain 27.1 million
  • Diarrhea 5.6 million
  • Vomiting 5.5 million
  • Nausea 4.7 million
  • Bleeding 3.6 million

Most Common Diagnosis from Hospital Admissions in 2012 (Table 5):

  • GI hemorrhage 507,440 admissions
  • Cholelithiasis with cholecystitis 389,180 admissions
  • Acute pancreatitis 275,170 admissions
  • Intestinal obstruction 256,775 admissions
  • Appendicitis 248,080 admissions
  • Chronic liver disease/viral hepatitis 243,170 admissions

Causes of Death in U.S. in 2012 (Table 7):

  • Colorectal cancer 51,139
  • Pancreatic cancer 38,797
  • Liver/bile duct cancer 22,973
  • Cirrhosis 17,495
  • Alcoholic liver disease 17,419
Gastroenterology Cover

Gastroenterology Cover

Hepatitis C Cure: Too Late for Many

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Before the recent vast improvements in hepatitis C virus (HCV) treatment, there had been a number of studies predicting a huge increase in HCV-related mortality due to hepatocellular carcinoma (HCC) and cirrhosis.

Despite the optimism that have come with the new treatments, the most recent data (LA Beste, et al. Gastroenterol 2015; 149: 1471-82) continue to predict a huge and increasing burden of chronic liver disease due to HCV.

The authors used a national retrospective cohort of Veteran Affairs (VA) patients with cirrhosis (n=129,998) or HCC (n=21,326) from 2001-13.  They identified an increasing proportion of cirrhosis and HCC during that timeframe.

Key findings:

  • From 2001 to 2013, cirrhosis prevalence nearly doubled (664 –>1058 per 100,000 enrollees) driven by HCV and nonalcoholic fatty liver disease; deaths due to cirrhosis also increased from 83 to 126 per 100,000 patient years
  • From 2001 to 2013, HCC incidence increased 2.5-fold from 17 to 45 per 100,000 patient-years and HCC mortality tripled from 13 to 37 per 100,000 patient-years.  HCC incidence was driven overwhelmingly by HCV.
  • Based on current trends, cirrhosis prevalence will peak in 2021 according to the authors, though they acknowledge that patients from the VA may not be representative of the population at large and that the study has inherent weaknesses due to computerized data collection in this retrospective study.

My take: Despite dramatic improvements in HCV treatment, sadly, it is still going to get a lot worse with regard to disease burden & mortality from HCV before it will improve.

Briefly noted: F Negro. Gastroenterol 2015; 149: 1345-60.  “Extrahepatic morbidity and mortality of chronic hepatitis C”  This review article discusses diabetes, cardiovascular manifestations of HCV, fatigue, cognitive impairment, mixed cryoglobulinemia, and non-hodgkin lymphoma.

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Chattanooga Aquarium

Chattanooga Aquarium

Journals Supplanting Textbooks: Managing Liver Disease

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Between Journals and online resources, textbooks are increasingly less useful.  Case in point -this past month, Clinical Gastroenterology and Hepatology published a special issue: The Art and Science of Managing Liver Disease.  Some of the articles are excellent reviews.

Screen Shot 2015-11-21 at 5.35.44 PM

With autoimmune hepatitis (AIH), the authors make a number of useful points and concisely summarized diagnosis and management.  A few points:

  • Anti-soluble liver antigen/liver-pancreas (SLA/LP) and Asialoglycoprotein receptor (ASGPR) useful in diagnosis of AIH type 1 or 2 and is prognostic for severe disease.
  • In U.S. current guidelines suggest an azathioprine dose of 50 mg (for adults) whereas in Europe the dose is typically 1-2 mg/kg/day.  The authors suggest that the U.S. guidelines could lead to undertreatment, particularly with increasing rates of obesity.
  • The authors state that routine “testing for TPMT deficiency before AZA treatment of AIH is unnecessary, because severe TPMT deficiency occurs in 0.3%-0.5% of the general population and does not invariably cause AZA-induced bone marrow toxicity.” [I will probably continue to check TPMT activity.] They do recommend TPMT testing in cirrhotic patients and those with cytopenias.
  • The authors note that successful long-term withdrawal can occur in 19-40% but recommend biochemical remission (>12-24 months) and histologic remission.  They caution against withdrawal in patients after a relapse due to increased risks of progression to cirrhosis and/or death.
  • When discussing alternative therapies, the authors note that mycophenolate mofetil (MMF) is typically effective for patients intolerant to AZA but not likely to work in AZA nonresponders.
  • Alternative agents reviewed included tacrolimus, cyclosporine, sirolimus/everolimus, rituximab, and infliximab.

Other topics in this issue included NAFLD, HCC, Varices, Hepatic encephalpathy, HBV, HCV, Acute-on-Chronic Liver Failure, PSC and Malignancy, DILI, and noninvasive imaging for liver fibrosis.