- Diffuse extensive acellular pink amorphous deposit (amyloid) is seen in the sinusoids and peri-sinusoidal space (space of Disse).
- Few atrophic liver-cell plates
- Sinusoids are markedly compressed by amyloid
- Inspissated bile is seen in hepatocytes (cholestasis).
- Globular amyloid deposits are not seen
- Blood vessels are apparent due to extensive amyloid deposition.
Practical points of Pathoclinics:
- Amyloidosis is characterized by accumulation of fibrillar glycoprotein, an abnormal form of normal serum proteins, in an extracellular matrix and vessel walls. Common causes of amyloidosis are plasma cell dyscrasias, paraproteinemia, chronic infections, chronic inflammatory processes like chronic inflammatory bowel disease, and rheumatoid diseases.
- Liver amyloidosis is most common in primary AL amyloidosis (approximately 70% of all cases). Primary AL amyloidosis is commonly associated with plasmacytoma, multiple myeloma or Waldenstrom macroglobulinemia and comprising of monoclonal light chains. Liver involvement primary AL amyloidosis can be diffuse or focal. Liver involvement is usually associated with advanced disease and has poor prognosis. Sinusoidal deposition is more common in primary AL amyloidosis; however, it is not a specific pattern.
- Secondary AA amyloidosis composed of SAA protein, an acute phase reactant, often associated with chronic infections and systemic diseases, such as rheumatoid arthritis. Vascular involvement is more common in secondary AA.
- Hereditary apolipoprotein A-I (Apo AI) amyloidosis is rare, most cases are misinterpreted as primary AL or secondary AA amyloidosis. It has mutations in apolipoprotein A1.
- LECT2 amyloidosis accounts for an approximately 25% of all hepatic amyloidosis. It is due to LECT2 protein deposition, in a globular pattern. Morphologically large circular globules, presents in the sinusoids or within the hepatocytes. Lamination may be seen in globules. Some cases have less intense congophilia and faint birefringence on Congo red stain. Similar globular deposition may be seen in primary AL or secondary AA amyloid. This globular amyloid may be the precursor of the sinusoid pattern of amyloid deposition.
- Clinically, hepatic amyloidosis may be asymptomatic or may present with non-specific symptoms like fatigue, vague abdominal pain, anorexia, early satiety, weight loss, nausea, and extrahepatic manifestations. Clinical diagnosis of Hepatic amyloidosis is difficult so, liver biopsy is usually required, though risk of bleeding is high due to amyloid deposition in liver. Significant hepatomegaly is also a risk factor for spontaneous liver rupture and intra-abdominal hemorrhage. On radiology, amyloid may present as an extensive nodularity, which can mimic metastatic disease.
- Bio-chemical investigation reveals only mild elevation of alkaline phosphatase and liver transaminases in most of the cases. However, some rare cases may present with rapid deterioration of liver function and progressive liver failure, so early biopsy is necessary for initiation of cause specific management.
- Hepatic amyloidosis in primary AL patients have significantly higher serum plasmin-α2-plasmin inhibitor complex (PIC) levels than patients without hepatic involvement. Amyloidosis in other organs have no significant increase in the serum PIC level. However, prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen degradation product (FDP) and thrombin-antithrombin complex (TAT) have no such discriminative value in the diagnosis of hepatic AL amyloidosis. The serum PIC level is also co-related with the hematological response of systemic AL amyloidosis.
- The histologic appearance of amyloid remains the same as other body sites. Amyloid appears as a paucicellular pink to amphophilic extracellular material. Hepatic involvement is minimal to massive degree (later seen in present case) with marked hepatocyte atrophy and impair blood flow, led to portal hypertension or cholestasis (later in present case). Amyloid deposition occurs in the sinusoids, beneath the space of Disse (common location in liver) in a linear or globular pattern, in the portal tracts, and in hepatic arteries. The mix patterns are often seen. Amyloid deposits in a linear pattern may mimic fibrosis. Isolated globular amyloid deposition may resemble ground-glass hepatocytes, inclusions, and pale bodies. Mild cases are easily missed on biopsy. Small arteries and arterioles in portal tracts appear thick and hyalinized in the absence of sinusoidal deposits, due to amyloid deposits especially in familial cases. Small amount of amyloid is difficult recognize on H&E stain, so careful examination of arteriole usually reveals the thickening of arterial walls in the absence of sinusoidal deposits. Macrophages and multinucleated giant cells may be seen around amyloid deposits. Portal fibrosis is mild degree only without advanced fibrosis.
- Congo red stain is the gold standard for diagnosis of amyloid, with salmon pink color under routine light microscopy and apple green birefringence under polarized light. Colour of the amyloid varies from yellow-green to blue-green depending upon the status of polarization. Thick sections are better for Congo red stain. Prolonged tissue fixation may reduce the intensity of Congo red stain. Use of potassium permanganate in tissue sections before Congo red stain can differentiate the primary AL versus secondary AA amyloid. Primary AL amyloid has no effect of potassium permanganate while secondary AA amyloid lost the affinity for Congo red stain after potassium permanganate.
- Glycoprotein P can help in the diagnosis of amyloid as it is present in all cases. Stain for immunoglobulin light chains (AL type), SAA (AA type), transthyretin and LECT2 are important for distinction of different types and causes of amyloidosis. Interpretation of kappa and lambda chain on immunohistochemistry is difficult due to extensive background staining. Globular amyloid can be highlighted with a Congo red stain or a leukocyte chemotactic factor 2 (LECT2) immunostain.
- Electron microscopic characteristic of amyloid is central electron-lucent core with randomly oriented, including some parallel arrangement, of non-branching fibrils of indefinite length and diameter ranges from 6 nm to 20 nm. Laser microdissection and mass spectrometry on formalin-fixed, paraffin-embedded tissues or cytology material is the most accurate method for identification of amyloid subtype.
- Amorphous deposits in peri-sinusoidal and portal areas, like amyloid, also seen in light chain deposit disease. Immunoglobulin light chain (kappa or lambda) is usually identified by immunochemistry. Immunoglobulin light chains differ from amyloid by absence of characteristic apple-green birefringence after Congo red staining, which is a characteristic feature of amyloid. On electron microscopy, these light chains appear homogenous and granular. Rare cases may show both amyloid and light chain deposits in the same patient.
- Un-intentional weight loss, vague abdominal pain, hepatomegaly, unexplained elevated serum alkaline phosphatase level, proteinuria especially in old age individuals should raise the clinical suspicion for amyloidosis.
- Treatment of plasmacytoma or secondary causes like rheumatoid disease is the specific management. Liver transplant is required in massive involvement or in some hereditary cases of amyloidosis.
- Extensive amyloid deposition along with cholestasis, portal hypertension and congestive heart failure are adverse prognostic indicators. Overall hepatic amyloidosis has poor prognosis.
Ishiguro K, Hayashi T, Yokoyama Y, Aoki Y, Onodera K, Ikeda H, Ishida T, Nakase H. Elevation of Plasmin-α2-plasmin Inhibitor Complex Predicts the Diagnosis of Systemic AL Amyloidosis in Patients with Monoclonal Protein. Intern Med. 2018 Mar 15;57(6):783-788. doi: 10.2169/internalmedicine.8999-17. Epub 2017 Oct 11. PMID: 29021469; PMCID: PMC5891514.