How Obesity Permeates Transplant Medicine

A Mathur. Liver Transplantation 2023; 29: 465-466. Open Access! Salvaging the fatty liver for transplant: is short duration NMP enough? (ed)

 “As of 2020, the Center for Disease Control (CDC) notes that 40% of the ~258 million US adults suffer from obesity. This represents just more than a 100 million people suffering from obesity. In addition, about 23 million people suffer from severe obesity with a body mass index >40 kg/m2.” Fatty liver disease (aka NAFLD), driven primarily by obesity, is a leading cause of liver transplantation. In addition, fatty liver disease is impacting the ability to treat liver failure.

“The end result of this epidemic is that we are identifying a greater proportion of organ donors with varying degrees of liver steatosis. Transplantation of steatotic livers is associated with an increased degree of ischemia-reperfusion injury (IRI) and release of inflammatory cytokines from the graft. The consequences of this can range from severe reperfusion syndromes with immediate vasoplegia and circulatory collapse to distant organ dysfunction with acute kidney injury, liver allograft dysfunction, and primary nonfunction (PNF).”

In order to try to identify suitable liver organs for transplantation, researchers are trying to identify strategies to utilize steatotic grafts safely. Patrono et al (Liver Transplantation 2023; 29: 508-502) examined the feasibility of using normothermic machine perfusion (NMP) in the setting of macrovesicular steatosis (MaS) ≥30%. They identified 10 patients who had liver transplants using NMP in patients with MaS ≥30%; 4 additional organs were not used despite NMP. 8 of 10 patients showed good liver function, representing 57% (8 of 14) of NMP fatty organs.

Another study in the same issue (NB Ha et al. Liver Transplantation 2023; 29: 476-484) showed that patients with sarcopenic obesity (=low muscle mass obesity) had high waitlist mortality of 40% compared to 21% and 12% for those with sarcopenia without obesity and for those with obesity without sarcopenia, respectively.

My take: Obesity increases the risk of fatty liver associated cirrhosis/liver failure, and is impacting the availability of suitable organs for those in need. Furthermore, in those with obesity, the presence of sarcopenia increases the risk of death on transplant waitlist.

Tucson Botanical Gardens

Practice Guidance on Wilson Disease (AASLD)

View from Mt Lemmon, Tucson AZ

ML Schilsky et al. Hepatology 2023; 77: 1428-1455. Open Access! A multidisciplinary approach to the diagnosis and management of Wilson disease: Executive summary of the 2022 Practice Guidance on Wilson disease from the American Association for the Study of Liver Diseases

This article is an excellent review of Wilson disease (WD). It reviews clinical manifestations, disorders with overlapping findings and recommendations for diagnosis/management. “This executive summary provides a condensed overview, including the clinical algorithms, tables, and full complement of guidance statements.” Though this ‘summary’ is a lengthy publication, “the full Guidance document with comprehensive text, complete references, and supplementary materials (“A Multidisciplinary Approach to the Diagnosis and Management of Wilson Disease: 2022 Practice Guidance on Wilson Disease from the American Association for the Study of Liver Diseases”) is available on the American Association for the Study of Liver Diseases (AASLD) website (”

Some of the recommendations:

The Leipzig score for diagnosis of Wilson disease may aid in diagnosis

My take: This is a useful guidance and the tables/algorithms should help with both diagnosis and treatment adjustment. In my limited experience with WD, I have had a lot of difficulty with adherence to treatment in the small sample of patients under my care.

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Is It a Mistake to Use Budesonide for Autoimmune Hepatitis?

A Diaz-Gonzalez et al. Hepatology 2023; 77: 1095-1105. Open Access! Budesonide as first-line treatment in patients with autoimmune hepatitis seems inferior to standard predniso(lo)ne administration

Background: AASLD guidelines also suggest the use of budesonide with azathioprine as an alternative agent (to prednisone with azathioprine) in patients without cirrhosis or a severe acute presentation.1–3 However, particularly in pediatrics, there is concern that it is not as effective.

Methods: This was a retrospective, multicenter study of 105 naive AIH patients treated with budesonide as the first-line drug. The control group included 276 patients treated with prednisone.

Key findings:

  • The biochemical response (BR) rate was significantly higher in patients treated with prednisone (87% vs. 49% of patients with budesonide, p < 0.001). BR was defined as normalization of both serum transaminases and IgG.
  • The probability of achieving BR was significantly lower in the budesonide group (OR = 0.20) at any time during follow-up, and at 6 (OR = 0.51) and 12 months after starting treatment (0.41)
  • Prednisone treatment was significantly associated with a higher risk of adverse events (24.2% vs. 15.9%). These differences vanished when patients with cirrhosis were excluded from the analysis, showing a similar incidence of AEs in both groups (p = 0.119). Of the specific adverse effects, only the presence of osteoporosis was significantly higher in the prednisone group (mainly in those older than 60 years)
  • The authors note that budesonide was “only indicated in 5.4% of patients newly diagnosed with AIH… Budesonide was mainly employed in patients with low baseline transaminases, suggesting that this drug is preferred in patients with less severe disease.”

My take: “The use of budesonide in the real-life setting was low and was associated with a lower probability of achieving BR with respect to prednisone.” It likely needs to be restricted to those with mild disease, and those with adverse events with prednisone. Cost is less of an issue as budesonide can be obtained as a generic (Mark Cuban Costplus pharmacy: Budesonide).

Related blog posts:

AGA Practice Update: Acute Hepatic Porphyrias

B Wang et al. Gastroenterol 2023; 164: 484-491. Open Access! AGA Clinical Practice Update on Diagnosis and Management of Acute Hepatic Porphyrias: Expert Review

Overall, acute hepatic porphyrias (AHP) are rare disorders. “Acute intermittent porphyria is the most common type of AHP, with an estimated prevalence of patients with symptoms of
approximately 1 in 100,000. The major clinical presentation involves attacks of severe pain, usually abdominal and generalized, without peritoneal signs or abnormalities on cross-sectional imaging…The screening tests of choice include random urine porphobilinogen and d-aminolevulinic acid corrected to creatinine.”

“All patients with elevations in urinary porphobilinogen and/or d-aminolevulinic acid should initially be presumed to have AHP. The cornerstones of management include discontinuation of porphyrinogenic drugs and chemicals, administration of oral or intravenous dextrose and
intravenous hemin, and use of analgesics and antiemetics. Diagnosis of AHP type can be confirmed after initial treatment by genetic testing for pathogenic variants in HMBS, CPOX, PPOX, and ALAD genes.”

Some of the best practice advice:

  • Women aged 15–50 years with unexplained, recurrent severe abdominal pain without a clear etiology after an initial workup should be considered for screening for an AHP.
  • Initial diagnosis of AHP should be made by biochemical testing measuring d-aminolevulinic acid, porphobilinogen, and creatinine on a random urine sample.
  • Genetic testing should be used to confirm the diagnosis of AHP in patients with positive
    biochemical testing.
  • Acute attacks of AHP that are severe enough to require hospital admission should
    be treated with intravenous hemin, given daily, preferably into a high-flow central vein

Related blog posts:

Genetic Testing to Figure Out Drug Reactions

P Nicoletti et al. Gastroenterol 2023; 164: 454-466. Open Access! Identification of Reduced ERAP2 Expression and a Novel HLA Allele as Components of a Risk Score for Susceptibility to Liver Injury Due to Amoxicillin-Clavulanate

Key findings:

  • Transcriptome-wide association study revealed a significant association of AC-DILI risk with reduced liver expression of ERAP2 (P = 3.7 × 10–7), coding for an aminopeptidase involved in antigen presentation
  • “We also identified HLA-B∗15:18 as a novel AC-DILI risk factor in both discovery (OR, 4.19) and validation (OR, 7.78) cohorts”
  • A genetic risk score incorporating rs1363907, rs2476601, HLA-B∗15:18, HLA-A∗02:01, and HLA-DRB1∗15:01, was highly predictive of AC-DILI risk when cases were analyzed against both general population and non–AC-DILI control cohorts.
  • This genetic risk score does not apply to amoxicillin. “Clavulanate has long been considered the main component causing Amoxicillin-Clavulanate-DILI (LiverTox”
  • While the genetic risk score has high specificity, it is not highly sensitive. “Our multimarker model based on the 5 risk alleles predicted approximately 13% of the total risk for AC-DILI, which is approximately one-third of the total DILI risk that has previously been attributed to common genetic variants (approximately 40%)”

My take: In cases of suspected AC-DILI, identifying an abnormal genetic risk could help confirm the diagnosis. However, due to low sensitivity it is not likely to gain widespread clinical use.

Graphical Abstract:

Related blog posts:

Liver Updates: Statin Protection from HCC, PSVD -new name, novel finding and Hypothyroidism with Hepatic Hemangiomas

B Zou et al. Clin Gastroenterol Hepatol 2023; 21: 435-444. Open Access! Statin Use and Reduced Hepatocellular Carcinoma Risk in Patients With Nonalcoholic Fatty Liver Disease

This study, in agreement with prior studies of individuals with chronic liver disease, showed that statin use is associated with a lower risk of hepatocellular carcinoma in NAFLD as well, with a Hazard Ratio of 0.47 in a database with 272,431 adults with NAFLD. The authors note the concern about hepatotoxicity from statins; however, “severe liver injury from statins is fairly low. Indeed, the incidence of lovastatin-associated fulminant liver failure is about 2 in a million users.”

Related blog posts:

J Shan et al. Hepatology 2023; 77:501-511. Open access! Genetic predisposition to porto‐sinusoidal vascular disorder: A functional genomic‐based, multigenerational family study

Porto‐sinusoidal vascular disorder (PSVD; also previously described as idiopathic noncirrhotic portal hypertension [NCPH]…”is a group of liver vascular diseases featuring lesions encompassing the portal venules and sinusoids unaccompanied by cirrhosis, irrespective of the presence/absence of portal hypertension. It can occur secondary to coagulation disorders or insult by toxic agents. However, the cause of PSVD remains unknown in most cases.”

Key findings:

  • In a group of 4 patients, a novel heterozygous mutation in the FCHSD1 gene was identified but not in 2 familial controls.
  • When this variant was introduced in mice using CRISPR, ” Nine out of the 15 mice carrying the human FCHSD1 R183W variant mimicked the phenotype of human PSVD, including splenomegaly and enlarged portal vein.”
  • Aberrant FCHSD1 structure and function led to mTOR pathway overactivation

Related blog post: Time to Adjust the Knowledge Doubling Curve in Hepatology

MA Siano et al. JPGN Reports. 2022; 3(4):p e270,.  Consumptive Hypothyroidism due to Hepatic Hemangiomas: A Case Series and Review of the Literature

“Consumptive hypothyroidism (CH) is a rare form of hypothyroidism due to thyroid hormone inactivating enzyme type 3 (Deiodinase) overexpressed by hepatic/hepatic and cutaneous hemangiomas, and occasionally by some other extrahepatic visceral hemangiomas…Pediatric hepatologists should recognize the importance of periodical assessments of thyroid function in patients with hepatic hemangiomas”

“MRI of the abdomen in one of our patients (patient 1), before (A) and after (B) 19 months of treatment with propranolol/10 months of treatment with levothyroxine. The T2-weighted axial MRI images shows the regression of a diffuse infantile hepatichemangioma with innumerable T2 hyperintense masses throughout the liver with central hypointense central regions.”

Stratifying the Risk of Asymptomatic Gallstones

G Morris-Stiff et al. Clin Gastroenterol Hepatol 2023; 21: 319=327. The Natural History of Asymptomatic Gallstones: A Longitudinal Study and Prediction Model

Using a retrospective cohort design with 22,257 patients (51% female) with a mean age of 61 years, Key Findings:

  • There was a 2% per year rate of developing symptomatic gallstones
  • Overall, 14.5% developed symptoms with a median followup of 4.6 years
  • Cumulative incidence of becoming symptomatic: 10.1% at 5 years, 21.5% at 10 years, and 32.6% at 15 years
  • The strongest predictors of developing SGs were female gender (hazard ratio [HR], 1.50), younger age (HR per 5 years, 1.15), multiple stones (HR, 2.42), gallbladder polyps (HR, 2.55), large stones (>9 mm) (HR, 2.03), and chronic hemolytic anemia (HR, 1.90). Elevated BMI was associated with increase risk; for example a BMI >40 had a HR of 1.60.
  • Statin use was associated with a reduced risk of with HR 0.61

My take: This large retrospective study of adults indicates that if given enough time, more than 1/3rd of individuals will develop symptomatic gallstones. Surgical intervention should be considered in those with significant risk factors.

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Dog’s viewpoint at the Chattahoochee River in Sandy Springs, GA

Why Telehealth Will Not Solve Health Care Disparities: Liver Care Experience

JB Henson et al. Hepatology 2023; 77: 176-185. Access to technology to support telehealth in areas without specialty care for liver disease

Key finding: Technology access was lowest in areas with low access to care and the highest burden of liver‐related mortality.

Editorial: S Wadhwani, JC Lai. Hepatology 2023; 77: 13-14. Open Access! The digital determinants of liver disease

An excerpt:

The authors found that counties with decreased access to gastroenterologists and liver transplant centers had increased county‐level liver‐related mortality. These counties tended to have residents who were more likely to be living in poverty, have lower educational attainment, have less access to primary care, and be living in a rural location. These same counties were less likely to have access to the high‐quality connectivity necessary to engage in telehealth appointments, demonstrating that telehealth in its current iteration will be unable to overcome health inequities in liver disease. For telehealth to be a viable solution to overcoming disparities in liver‐related mortality, the United States will need to tackle the “digital divide.”

My take: The same patients who have trouble seeing a liver specialist due to distance, transportation issues, and poverty are much less likely to have a good internet connection. Without this digital access, telehealth cannot help solve the disparity in care.

Related blog posts:

Favorite Posts 2022

Thank you to those who have helped me this past year with this blog –colleagues, friends and family. Wishing all of you a good 2023. Here are some of my favorite posts from this past year:





Health Policy:


New Age for Hepatitis B Therapies

M-F Yuen et al. NEJM 2022; 387; 1957-1968. Efficacy and Safety of Bepirovirsen in Chronic Hepatitis B Infection

This study is nicely summarized in a “quick take” video and also reviewed in an accompanying editorial by J Hoofnagle (pages: 1996-1998).

In this phase 2b, randomized, investigator-unblinded trial involving 457 participants with chronic HBV infection (1/2 receiving nucleotide analogue (NA) therapy), the authors evaluated bepirovirsen is an antisense oligonucleotide that targets all hepatitis B virus (HBV) messenger RNAs and acts to decrease levels of viral proteins.

Background: HBV infection affects 4% of worldwide population and has a prevalence of 0.3% in the U.S. Worldwide, HBV causes more than 1/2 million deaths each year.

Key finding:

Mechanism of Action: Bepirovirsen is an antisense oligonucleotide that targets all hepatitis B virus (HBV) messenger RNAs and acts to decrease levels of viral proteins.

Current therapies (like entecavir and tenofovir) are able to suppress viral replication but have low rates of clearance of HBsAg and most often HBV relapses when medications are stopped. This is due to covalently closed circular DNA which can persist in hepatocytes despite these medications.

In Dr. Hoofnagle’s editorial, he notes that bepirovirsen is one of several RNA-based HBV therapies that are being pursued. There are also “the more malleable small interfering RNA molecules (“-sirans”) are currently in early-phase clinical trials.”

My take: While these studies point to new therapies for those afflicted with HBV infection, the best strategy for reducing HBV mortality and morbidity still relies of wide-scale use of the highly effective HBV vaccine.