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A woman with Mahvash disease presented with portal hypertension that necessitated liver transplantation; the liver complications observed in this case report distinguish it from what's more typically seen in patients with this condition.

The 27-year-old woman presented with mildly elevated aminotransferase levels and chronic pancreatitis after having experienced three episodes of hematemesis. Although her imaging initially suggested possible hepatic cirrhosis, she had "no notable history of alcohol use," and a liver biopsy showed no evidence of cirrhosis, instead showing cholestasis with patchy perisinusoidal fibrosis and sinusoidal dilation, reported Daniel S. Lefler, MD, of the Perelman School of Medicine at the University of Pennsylvania in Philadelphia, and colleagues.

A biopsy of her pancreas showed a grade 1 neuroendocrine tumor, and the patient had serum glucagon levels over 25,000 pg/mL, leading the medical team to treat her with monthly octreotide injections for presumptive glucagonoma, they noted in the .

Over the next year, the patient was seen four more times, once with hyperammonemia requiring admission to the intensive care unit. Each time, hemodialysis resolved her symptoms and reduced ammonia levels but did not normalize them or change glucagon levels. The patient's lack of standard glucagonoma syndrome symptoms led to suspicion of Mahvash syndrome, which was confirmed when genetic testing revealed two null variants in GCGR.

Mahvash disease, caused by a mutation in both alleles of GCGR, is an extremely rare condition described in only about a dozen case reports in the literature and estimated to have a prevalence no higher than four cases per million.

Without a functioning glucagon receptor, the loss of glucagon signaling in the liver results in an abnormally high concentration of amino acids in the blood that then triggers the pancreas to produce an overabundance of pancreatic α-cells, the endocrine cells that secrete glucagon. This α-cell hyperplasia most often leads to extremely high glucagon levels (without glucagonoma syndrome) and pancreatic neuroendocrine tumors, Lefler and team explained.

"Although the patient described here has the typical signs of Mahvash disease, the additional findings of portal hypertension and portosystemic encephalopathy make her presentation unique even among rare company," the authors wrote. "Our study underscores the importance of an underlying hepatic pathophysiology in the context of a traditional focus on the pancreatic complications of Mahvash disease."

Management can include somatostatin analogues to suppress hyperglucagonemia -- albeit without adequate efficacy data -- and pancreatectomy, which similarly lacks reliable criteria for its indication. But in this case, "the special part is the liver pathology, which really has not been described before," Lefler told 蜜芽app.

A key feature of that liver pathology was portosinusoidal vascular disease (PSVD), a recently christened nomenclature for portal hypertension without cirrhosis.

"It's a linked physiology, so they [the pancreas and liver] both cause problems," since the hormonal feedback loop between the pancreas and the liver doesn't exist without the functioning glucagon receptors, Lefler explained, but "the liver-predominant presentation and the symptomatology that came along with the portal hypertension" made this case novel.

Different GCGR mutations cause different levels of dysfunction, he noted, and the authors suspected that this patient's case was so severe because the pair of GCGR mutations she had were particularly devastating to glucagon receptor function.

Because of the patient's PSVD and portosystemic encephalopathy, and "previous evidence of the efficacy of liver transplantation in other metabolic disorders," the patient underwent a liver transplant 28 months after initial presentation, Lefler and team wrote. Since transplantation, MRI scans have shown reductions in pancreas size, pancreatic hyperplasia, and neuroendocrine tumor size. Both glucagon and ammonia levels have also dramatically decreased, and encephalopathy resolved.

The clinical take-home message is that Mahvash disease should be considered for patients with massive pancreaticomegaly whose etiology can't be otherwise determined, Lefler said. "It's maybe under-recognized because it is so rare," he added, but it's important that Mahvash disease, detectable through genetic testing, be part of the differential in the presence of massive idiopathic pancreaticomegaly and pancreatic neuroendocrine tumors.

In an accompanying "" editorial, Pramod K. Mistry, MD, PhD, and Guadalupe Garcia‑Tsao, MD, both of Yale School of Medicine in New Haven, Connecticut, wrote that although the pathogenesis of PSVD is not known, a wide range of potential mediators for it exist, including "medications or toxins (e.g., oxaliplatin), immunologic disorders, infections, prothrombotic conditions, genetic disorders (e.g., cystic fibrosis, polycystic liver disease, and Turner syndrome), and a recently described syndrome associated with DGUOK and GIMAP5 gene defects."

In this case, the patient's extremely high glucagon levels in portal blood "could have produced the 'first hit' in the form of the capillarization of liver sinusoidal endothelial cells," which contain non-GCGR receptors activated by glucagon that itself regulates portal pressure, Mistry and Garcia-Tsao noted.

The dysfunction seen in the patient's urea cycle likely resulted from her elevated arginine levels, since arginine is "the precursor of nitric oxide, which is implicated in splanchnic vasodilatation -- a pathogenic driver of portal hypertension," they added. The liver transplant provided functioning GCGR, thereby restoring glucagon signaling and reversing the metabolic disorder, while also providing the normalized hepatic microvasculature needed to reverse the portal hypertension.

"For this patient, liver transplantation represented a form of curative 'surgical' gene therapy," Mistry and Garcia‐Tsao concluded. "Thus, deft management of this patient's Mahvash disease is akin to lifesaving procedures in other inborn errors of metabolism."

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