Introduction

Sinusoidal obstruction syndrome (SOS)/veno-occlusive disease (VOD) is a serious complication after hematopoietic stem cell transplantation (HSCT). The diagnostic criteria of SOS/VOD were based on clinical findings, recently, ultrasonography (US) has been suggested as one of modalities to assess hepatomegaly and ascites to diagnose SOS/VOD in pediatric patients¹. Considering the pathogenesis of SOS/VOD, that is endothelial damage in sinusoid leading to impairment of blood flow and congestion. If detecting alteration of blood flow by US is possible, US would be an effective tool. We previously reported the usefulness of original US scoring system, which includes assessing hepatomegaly, ascites, and blood flow alteration. It is called Hokkaido US-based scoring system (HokUS) -10²/6³ in diagnosing SOS/VOD. However, the usefulness of HokUS-10/6 for diagnosing SOS/VOD in pediatric patients remains unclear.

Aims & Methods

To elucidate diagnostic performance of HokUS-10/6 for SOS/VOD in pediatric patients.The patients who underwent HSCT from Jan. 2008 to Feb. 2023 in our institution were enrolled. HokUS-10/6 were applied to the patients before HSCT and on day 14, 28 or when the signs of SOS/VOD appeared after HSCT. SOS/VOD was clinically diagnosed by the modified Seattle⁴ or the Baltimore criteria⁵ or the European Society for Blood and Marrow Transplantation criteria in pediatric patients⁵. HokUS-10 consists of 10 parameters: 1) hepatomegaly in the left lobe and 2) right lobe, 3) dilatation of the main portal vein (PV), 4) hepatofugal flow in the main PV, 5) decreased velocity of the PV, 6) dilatation of the para-umbilical vein (PUV), 7) appearance of blood flow signal in the PUV, 8) gallbladder (GB) wall thickening, 9) ascites, and 10) increased resistive index of the hepatic artery (HA-RI). In HokUS-6, presence of ascites is mandatory. When ascites was detected, 6 parameters were evaluated: moderate amount of ascites, appearance of PUV blood flow signal, GB wall thickening, PV dilatation, PV velocity decrease, and HA-RI increase. The severity is divided into five categories: grade 1 = mild; grade 2 = moderate; grade 3 = severe; grade 4 = very severe; and grade 5 = death⁵. A receiver operating characteristic (ROC) curve was used to evaluate the diagnostic accuracy.

Results

In total 101 patients (male 65 and female 36), median age 6 (range 0 to 16), were analyzed, of whom 13 patients (12.9%) were diagnosed as SOS/VOD at a median of 28 days (range, 3-102 days) after HSCT. Three (20%) patients showed hyperbilirubinemia (> 2 mg/dl), while all patients had transfusion-refractory thrombocytopenia, hepatomegaly, and ascites. When cut-off value of HokUS-10 and 6 were set 4 and 2, highest AUC was calculated as 0.981 (95% CI : 0.958 - 1) and 0.966 (95% CI : 0.930 - 1), respectively. The sensitivity, specificity, positive predictive value, and negative predictive value for diagnosing SOS/VOD were, 100%, 85.2%, 50.0%, and 100% by HokUS-10, and 84.6%, 95.5%, 73.3%, and 99.7% by HokUS-6, respectively. Using cut off value set at 5 same as adults in HokUS-10, sensitivity declined to 84.6% (two patients showed false negativity). HokUS-10/6 detection of SOS/VOD preceded five days its clinical diagnosis in 1 case, clinical diagnosis was made following US detection on the same day in the other cases. The numbers of patients with SOS/VOD grade 1, 2, 3, 4 and 5 were 0, 0, 2, 11 and 0, respectively.

Conclusion

HokUS-10/6 scoring system showed good diagnostic performance in pediatric patients same as in adults. The cut off value of HokUS-10 would be better to use 4 rather than 5 in pediatric patients.

References

1. Mohty M, et al. Bone Marrow Transplant 2016; 51(7): 906-912.
2. Nishida M, et al. Biol Blood Marrow Transplant 2018; 24(9): 1896-1900.
3. Nishida M, et al. Int J Hematol 2021; 114(1): 94-101.
4. Jones RJ, et al. Transplantation 1987; 44(6): 778-783.
5. McDonald GB, et al. Ann Intern Med 1993; 118(4): 255-267.

Disclosure

Mutsumi Nishida has received a research grant and a speaker fee from Nippon Shinyaku, and a speaker fee from Pfizer. Takanori Teshima has received research grants and speaker fees from Chugai, Kyowa Kirin, Nippon Shinyaku, Sumitomo Pharma and Astellas, research grants from Fuji Pharma, Asahi Kasei Pharma, Eisai, Ono, Shionogi, Priothera SAS and Luca Science, speaker fees from AbbVie, Novartis, Bristol-Myers Squibb, Merck Sharp & Dohme, Celgene and Janssen, and participation on a Data Safety Monitoring Board or Advisory Board at Novartis, Meiji Seika Pharma, Daiichi Sankyo, Asahi Kasei Pharma, Astellas, AstraZeneca, Takeda, Janssen, Roche Diagnostics, Sumitomo Pharma, Celgene and Sanofi. Rest of the authors declare that they have no conflict of interest.

Clinical Case Summary

We present a 27-year-old man with sickle cell disease (SCD), treated with hydroxyurea. Over the previous year, he was hospitalized three times due to vaso-occlusive crisis (VOC). He was referred to Gastroenterology for persistent abnormal liver tests for the last five years, which exhibited a cholestatic pattern and showed further worsening during VOC. AST was 2 times the upper limit of normal (ULN), ALT was normal, alkaline phosphatase (ALP) 4 times ULN, and total bilirubin 3-4 times ULN. After the last VOC, cholestasis worsened with conjugated hyperbilirrubinemia up to 10 times ULN and ALP up to 6-7 times ULN with ALT 2 times ULN and AST 5 times ULN. Coagulation was normal.
Abdominal ultrasound showed hepatomegaly with normal blood flow on doppler study. Abdominal MRI also revealed a heterogeneous liver with regenerative nodules, but no bile duct dilation.
Further investigation ruled out alcohol or drug use. ANA was positive (1:320), IgG was elevated (2230 mg/dL), suggesting polyclonal gammopathy, while other autoimmune markers were negative. Ferritin was elevated with normal transferrin saturation. Urinary copper and ceruloplasmin were increased, likely reflecting an acute-phase response. Viral serologies were negative.
A liver biopsy revealed portal fibrosis with porto-central bridging and significant fibrosis in the spaces of Disse. Dilated sinusoids were obstructed by abnormally shaped erythrocytes. These findings are consistent with chronic hepatitis secondary to chronic sinusoidal obstruction syndrome, likely due to recurrent VOC.
The case was discussed with both his hematologist and a liver transplant centre. He is now awaiting enrollment in a clinical trial for genetic therapy for SCD.
SCD can lead to liver damage through multiple mechanisms, and these complications are often underrecognized. We present this case due to the severity of the chronic liver disease and the rare occurrence of chronic sinusoidal obstruction syndrome associated with SCD.

References

This case will be illustrated with laboratory results, imaging studies, and liver biopsy images.

Clinical Case Summary

A 56-year-old woman was referred to tertial hospital for decompensated liver cirrhosis of unknown origin. She was slightly overweight (BMI 25.3) and denied alcohol consumption or any history of liver disease. Since childhood, she had been diagnosed with congenital ichthyosis, strabismus, and myopia, had a history of bilateral neurosensory hearing loss, arterial hypertension, and cataracts. Since 2016, she had been experiencing progressive muscle weakness, and intermittent speech impairment. The patient complained of eyes dryness, episodic joint and muscle pain, muscle weakness, general malaise, dizziness, dry and scaling skin. Physical examination revealed diffuse skin dryness, scaling and an enlarged abdomen. Radiological examination revealed a cirrhotic liver, splenomegaly and moderate ascites. The MELD score was 18 and the Child-Pugh - 9. Laboratory tests excluded Wilson's disease, autoimmune liver diseases, hemochromatosis, α-1 antitrypsin deficiency. Liver biopsy showed macro and microvesicular steatosis (>50% of hepatocytes with lipid vacuoles), hepatocytes ballooning and inflammation compatible with MAFLD related liver cirrhosis. In peripheral blood smear was detected multiple lipid vacuoles in the leukocytes cytoplasm, known as Jordan‘s anomaly, confirming Chanarin–Dorfman syndrome (CDS) - a rare autosomal recessive neutral lipid storage disease. Genetic testing confirm diagnosis and revealed a potentially pathogenic homozygous c.133+3A>C mutation in the ABHD5 gene. Due to progression of liver failure patient was referred for liver transplantation (LT) and liver was successfully transplanted in 2024.
The case showed that LT is a realistic option if liver function deteriorates in CDS. LT does not affect neurological, dermatological and other extrahepatic symptoms of the syndrome. In early post-transplant period attention should be paid to possible temporary worsening of heart failure due to cardiomyopathy associated with CDS.

Clinical Case Summary

Objective: Streptococcal toxic shock syndrome (STSS), caused by group A Streptococcus pyogenes (GAS), is characterized by shock and multiorgan failure and is associated with a high mortality rate. Organ transplant recipients are especially vulnerable due to immunosuppressive therapy. Although critical for graft survival, immunosuppression increases susceptibility to infections infections, the leading cause of morbidity and mortality early after liver transplantation (LT).
Summary of the case: A 69-year-old female on dual immunosuppressive regimen with mycophenolate mofetil (MMF) and tacrolimus due to LT in 2010 and chronic kidney disease, presented to the emergency department after tripping at home and injuring her neck with a wooden splinter from a chair. She developed progressive neck swelling and erythema, along with a maculopapular rash across her trunk and extremities (Figure 1). Contrast-enhanced CT scan showed a multiloculated abscess (59x32x85 mm) (Figure 2). Her leucocyte count was 22.4×10⁹/L, CRP 327.4 mg/L, and creatinine 233 μmol/L. Microbiological analysis tested positive for GAS, which was highly suggestive of STSS. She developed hypotension, dyspnea and fever prompting an urgent surgical drainage. MMF was discontinued and tacrolimus reduced. She was treated with cephazolin (2g every 8 hours for five days) and clindamycin (900mg IV every 8 hours for two weeks). Her skin rash slowly resolved, CRP decreased to 53.0 mg/L and kidney function improved. A CT scan confirmed resolution and showed no new abscess formation (Figure 2). After two years of follow-up, she is unremarkable.
Conclusion: STSS in organ transplant recipients is a complex clinical challenge that demands managing infections while minimizing the risk of graft rejection. This case highlights the importance of rapid interventions for infection complications in vulnerable population of transplanted patients even in the late course after transplant.

References

Figure 1. a) swollen and erythematous left side of the neck with a visible purulent secretion and enlarged lymph nodes in the submental, submandibular regions. b) maculopapular rash on the skin of the trunk and upper abdomen with desquamation in the flexural areas, primarily under the breasts
Figure 2. CT images of the neck with contrast in axial a), b), c) and coronal d), e), f) CT showing initially cellulitis and the multiple abscess collections of the left tonsile, submandibular space, levels II and III and abscess collection of the sternocleidomastoid muscle and later resolution of abscess.

Introduction

Caroli disease (CD) is a rare congenital disease defined by the presence of segmental dilations in the intrahepatic bile ducts. It is called Caroli syndrome (CS) when it is associated with liver fibrosis or cirrhosis. It is often diffuse, rarely localized to a single lobe of the liver.
The aim of this study was to describe the epidemiological, clinical and therapeutic aspects as well as the observed complications associated with this pathology

Aims & Methods

We collected patients followed for CD or CS in the gastroenterology department of the Tahar Maamouri University Hospital in Nabeul from January 2008 to December 2018. We retrospectively collected epidemiological, clinical, radiological, therapeutic and evolutionary data.

Results

We collected 8 patients: 4 men and 4 women whose average age was 64 years (38 -79 years). The circumstances of discovery were an acute cholangitis in two patients and biliary colic in six. The average time between the onset of symptoms and definitive diagnosis was 10 months with extremes ranging from 1 month to 10 years. A morphological assessment (abdominal ultrasound, abdominal CT or Biliary MRI) was carried out in all patients. It showed dilation of the intrahepatic bile ducts (IHBD) in all cases. It was diffuse in four cases and localized to the left in 4 cases. It was associated with intrahepatic stones in 50% of patients (N=4). Gallstone lithiasis was associated in 38% of cases (N=3). Polycystic kidney disease was observed in 25% of patients (N=2). All patients had normal renal function. Two patients had signs of portal hypertension consistent with a Caroli syndrome. In our series, complications were observed in 50% of cases such as: iterative attacks of acute cholangitis in two patients, acute pancreatitis due to a biliary lithiasis in one patient and a case of liver abscess in one patient. Episodes of cholangitis were controlled by appropriate antibiotic therapy and ursodeoxycholic acid was prescribed in 3 patients at a dose of 15 mg/kg/day for intrahepatic lithiasis. Surgical treatment was carried out in 4 patients, consisting of a left hepatectomy in 3 patients with localized disease and a choledocotomy with hepaticojejunal anastomosis in one patient for lithiasis of the main bile duct. Endoscopic sphincterotomy was performed in 2 patients: one for residual lithiasis of the common bile duct in and one as sequential treatment. The median follow-up was 84 months, two deaths were observed: one secondary to hepatocellular failure and the other secondary to uncontrolled septic shock. In our series there was no case of cholangiocarcinoma.

Conclusion

The diagnosis of CD is often late. It should be considered in the presence of abscesses or recurrent cholangitis associated with the dilatation of the bile ducts. Hepatectomy of localized forms protects against septic complications and degeneration. Liver transplantation remains to be developed to treat patients with a diffuse form.

Clinical Case Summary

A 36-year-old man with a history of chronic diarrhea was admitted with isolated oedemato-ascitic syndrome and general deterioration.On examination,he had conjunctival subicterus bilateral lower limb edema, thoracoabdominal collateral venous circulation and ascites.As part of the etiological work-up of the oedemato-ascitic syndrome,Cardiac and renal causes were ruled out.Chest X-ray showed a hilar opacity with tracheal retraction.GeneXpert test on sputum confirmed pulmonary tuberculosis.Paracentesis showed non-infected transudate ascites with a serum-ascites albumin gradient at 11 g/L.Blood tests showed microcytic hypochromic anemia,normal platelet count,and elevated liver tests with AST at 18 times the upper limit of normal (ULN), ALT at 11× ULN, alkaline phosphatase at 3.3× ULN,normal GGT,prothrombin time at 25%,and a direct hyperbilirubinemia of 24 mg/L.Viral serologies were negative.Serum protein electrophoresis showed a beta-gamma bridging pattern with hypergammaglobulinemia.Antinuclear antibodies were positive, while the remaining autoimmune panel and Wilson's disease screening were negative.Abdominal CT angiography showed hepatomegaly with hypertrophy of the caudate lobe,a “flip-flop” pattern,stenosis of the intrahepatic inferior vena cava, and non visualization of the hepatic veins confirming Budd-Chiari syndrome(BDS).The etiological work-up of the chronic diarrhea revealed negative HIV serology,normal TSH,and elevated IgA anti-transglutaminase antibodies.Ileocolonoscopy showed partial villous atrophy in the ileum,supporting the diagnosis of coeliac disease (CD).Given the radiological features suggestive of BDS,a thrombophilia work-up was performed and was negative.An autoimmune etiology related to CD was retained as the most likely cause of BDS.A gluten-free diet resolved the diarrhea.Anticoagulation was started, but persistent portal hypertension and difficulty maintaining therapeutic anticoagulation led to referral for a portosystemic shunt.

References

An actual image of the thoracoabdominal collateral venous circulation of the patient, and his abdominal CT angiography.