Interesting Case, September 2024 – Hans Popper Hepatopathology Society

Case contributed by, Brent K. Larson, DO
Associate Professor
Department of Pathology and Laboratory Medicine
Cedars-Sinai Medical Center
Los Angeles, CA 90048

Clinical History*
*some details from the clinical history have been modified to maintain patient privacy, though the substance of the case remains the same

A 44-year-old woman presented to the transplant hepatology clinic, referred for liver transplant evaluation after being diagnosed with a genetic disorder at an outside nephrology clinic. She initially came to medical attention with kidney stones approximately five years ago. In the ensuing years, she has had at least four instances of kidney stones requiring medical or surgical intervention. Two years ago, the patient presented with sudden-onset renal failure, and she has been on peritoneal dialysis since.

The patient’s only other significant medical condition is hypothyroidism. She has no history of any chronic liver disease and no family history of liver disease. She denies any history of alcohol usage, intravenous drug usage, tattoos, blood transfusions, or alcohol usage. She denies any features of portal hypertension, including ascites, confusion, edema, or melena/hematemesis. Her medications include levothyroxine, sevelamer, and a multivitamin. She denies using any other medications or supplements.

The patient has one brother and one sister that were diagnosed with abrupt-onset end-stage renal disease and started on dialysis in their 30s. Another brother died in his 30s on dialysis. She has no other relevant family history.

On examination, she had bilateral 2+ pitting lower extremity edema. No ascites was identified. Physical examination was otherwise unremarkable. Her body mass index (BMI) was 34.1 kg/m2 on presentation.

At presentation to the hepatology clinic, her ALT was 14 U/L (range: 0-55 U/L), AST was 29 U/L (range: 5-34 U/L), alkaline phosphatase was 473 (range: 40-150 U/L), total bilirubin was 0.3 mg/dL (range: 0.2-1.2 mg/dL), and albumin was 2.6 g/dL (range: 3.5-5.2 g/dL). Antibodies against hepatitis B virus (HBV) and hepatitis C virus (HCV) were negative. Anti-nuclear, anti-smooth muscle, anti-liver-kidney microsomal, and anti-mitochondrial antibodies were negative. Serum ceruloplasmin was within normal limits. Alpha-1-antitrypsin phenotyping demonstrated an MM phenotype.

Five and a half months after presentation to the transplant hepatology clinic, the patient underwent liver transplantation.

Gross examination of the explant specimen demonstrated a 1460 g liver, measuring up to 21.9 cm in greatest dimension. The capsule was smooth, and without nodularity (Figure 1). Cut surfaces revealed no focal lesions and no nodularity (Figure 2).

Microscopically, sections demonstrated intact lobular architecture (Figure 3, hematoxylin and eosin stains) with no fibrosis (Figure 4, Masson trichrome stain) and no hepatitis.

Rare polarizable crystals were present embedded in portal tracts and in vascular (mainly arterial) walls (Figures 5-7, hematoxylin and eosin stains, Figure 6 viewed under polarized light). Sections of the gallbladder and a pericholecystic lymph node (Figure 8, hematoxylin and eosin stains) also displayed scattered crystals.

Diagnosis

Primary hyperoxaluria, type 1

Discussion

Primary hyperoxaluria is a family of autosomal recessive disorders that all result in oxalate overproduction. Type 1 is the most common variant, which results from mutations in the AGXT gene that leads to deficient production of the alanine-glyoxylate aminotransferase enzyme. Alanine-glyoxylate aminotransferase is a peroxisomal enzyme located exclusively in hepatocytes.¹

Oxalate cannot be metabolized by the human body and is excreted by the kidneys. However, the profound overproduction of oxalate in primary hyperoxaluria overwhelms the ability of the kidneys to excrete oxalate, which binds to calcium to form calcium oxalate crystals. These crystals can be deposited in a variety of tissues throughout the body, but it is their propensity to occlude the renal tubules that brings patients to clinical attention.

Patients present with kidney stones, often in childhood. The stones are often composed of calcium oxalate monohydrate, or whewellite, that can be identified on biochemical analysis, emphasizing the importance of performing chemical analysis on kidney stones, particularly from pediatric patients. After repeated bouts of kidney stones, patients frequently present with sudden onset kidney failure. Serum and urine oxalate levels are indicative of the diagnosis. Historically, the diagnosis was confirmed by performing biochemical assays of enzyme activity on liver biopsies. But now that the mutations responsible for primary hyperoxaluria are well characterized, genetic testing is the definitive diagnostic test.

As with the current patient, most of the time that patients with type 1 primary hyperoxaluria reach the care of a hepatopathologist, the diagnosis has been established, though it is still possible for liver biopsies to be performed before the diagnosis is established. Unfortunately, diagnosis is frequently delayed, because the testing required to establish the diagnosis is not routine, and thus requires a high degree of suspicion on the clinicians’ part. In the past, treatment has primarily been symptomatic, via kidney transplantation. In the past few decades, liver transplantation, in combination with kidney transplantation, has been advocated to not only control symptoms, but to remove the primary dysfunction by replacing the enzyme-deficient hepatocytes with wild-type transplanted hepatocytes capable of producing alanine-glyoxylate aminotransferase. Because the transplantation is not actually done for liver dysfunction, serological testing is often normal or near-normal, as in the current patient. The slow degeneration of crystallized oxalate deposits throughout the body can lead to continued serum and urine elevations of oxalate for months or years after transplantation, as has been the case with the current patient.^2-3 At last follow-up three months after liver transplantation, serial kidney biopsies have demonstrated continued calcium oxalate accumulation in tubules and interstitium.

Type 1 primary hyperoxaluria is one of the few indications for liver transplantation other than decompensated cirrhosis from chronic liver disease. But transplantation for this indication is rare, and published reports detailing the histology are few. Several case reports have illustrated explanted livers with calcium oxalate crystals deposited in arterial walls,^4-7 unsurprising given that arterial walls are a preferred site of deposition throughout the body. A few cases have also demonstrated calcium oxalate crystals embedded in portal tract connective tissue,^{4, 6-7} as in the current case, and very rarely in hepatic parenchyma.⁵ Most early histological reports also did not demonstrate abnormalities of the hepatic architecture or significant inflammation,^{4-6, 8} which was also the case in the current patient. However, the only series publishing a systematic histological examination of livers explanted for treatment of type 1 hyperoxaluria demonstrated a wide range of histological findings, including portal fibrosis (8 of 18 patients), central fibrosis (5/18), bridging fibrosis (2/18), and cirrhosis (1/18). Hepatitis, predominantly portal, was also described in 7 of 18 explants. Crystals were only seen in 3 of 18. Iron deposition was seen in half of cases, as it was in the current case, unsurprising given that most patients have been on intensive dialysis regimens for years prior to liver transplantation.⁹ Of note, this series did not describe a detailed serological workup for chronic liver disease, and the possibility of concomitant liver disease leading to some of the changes catalogued cannot be excluded.

Learning Points

Primary hyperoxaluria is a family of conditions leading to deposition of calcium oxalate crystals throughout the body, eventually leading to kidney failure.
Type 1 primary hyperoxaluria is autosomal recessive and due to mutations in the AGXT gene that encodes the alanine-glyoxylate aminotransferase enzyme, an enzyme produced exclusively in the liver.
Liver transplantation can be curative for type 1 primary hyperoxaluria, and calcium oxalate crystals may be seen in arteries, portal tracts, and, less commonly, hepatic lobules. Crystals may also be found in other organs/tissues removed with the explanted liver (i.e., gallbladder, lymph nodes).
In addition to crystal deposition, a wide range of histological findings have been described in explanted livers, ranging from unremarkable liver to portal or lobular hepatitis, and with fibrosis ranging from none to advanced/cirrhosis.

References

Danpure CJ, Jennings PR. Peroxisomal alanine:glyoxylate aminotransferase deficiency in primary hyperoxaluria type I. FEBS Lett. 1986;201:20-24.
Duclaux-Loras R, Bacchetta J, Berthiller J, et al. Pediatric combined liver-kidney transplantation: a single-center experience of 18 cases. Pediatr Nephrol. 2016;31:1517-1529.
Cornell LD, Amer H, Viehman JK, et al. Posttransplant recurrence of calcium oxalate crystals in patients with primary hyperoxaluria: Incidence, risk factors, and effect on renal allograft function. Am J Transplant. 2022;22:85-95.
Dimashkieh H, Koehler A. Primary hyperoxaluria affecting the liver. Arch Pathol Lab Med. 2002;126:1250-1251.
Tanriover B, Mejia A, Foster SV, et al. Primary hyperoxaluria involving the liver and hepatic artery: images of an aggressive disease. Kidney Int. 2010;77:651.
Patra S, Vij M, Varghese JS, et al. Aggressive primary hyperoxaluria involving the liver in an adult. Liver Int. 2012;32:1564.
Kogiso T, Tokushige K, Hashimoto E, et al. Primary hyperoxaluria complicated with liver cirrhosis: A case report. Hepatol Res. 2015;45:1251-1255.
Kazama-Saegusa S, Kazama JJ, Sugaya H, et al. A case of late onset primary hyperoxaluria type I (PH-I) presented with black liver. Clin Nephrol. 1998;50:184-187.
Recker P, Beck BB, Sikora P, et al. Chronic liver disease and hepatic calcium-oxalate deposition in patients with primary hyperoxaluria. Sci Rep. 2022;12:16725.