Rare cause of deranged liver profile in pregnancy

Abstract

We present the case of a 33-year-old pregnant woman with an abnormal liver profile secondary to liver metastases from colon cancer. The patient presented in her third trimester with non-specific symptoms. Blood tests revealed a cholestatic liver picture, initially attributed to prurigo gravidarum. However, following a normal vaginal delivery, her symptoms persisted and the liver profile failed to return to baseline. This led to further investigations including a CT scan of the abdomen—revealing a transverse colonic tumour with extensive liver involvement. Biopsy of the liver confirmed an adenocarcinoma of colonic origin, and subsequently the patient underwent a right hemicolectomy followed by systemic chemotherapy.

Background

The diagnostic pathway for cancer in pregnancy and its management can be challenging and complex. Normal physiological changes in pregnancy can mask sinister signs. Diagnostic procedures including imaging (potential radiation exposure and contrast), biopsies, and/or surgery carry a significant risk. The clinician must have a high index of clinical suspicion before ordering investigations. This may result in a delayed diagnosis of malignancy, often at a more advanced stage. Since liver disease in pregnancy is present in up to 3% of patients,¹ clinicians need to be able to successfully differ benign from malignant causes. A multidisciplinary team approach is essential, ensuring timely management of potentially fatal diseases while minimising iatrogenic and unnecessary harm.

Case presentation

A 33-year-old woman presented during her third trimester of a previously uncomplicated pregnancy with fatigue, unintentional weight loss and a change in bowel habits. These were initially attributed to pregnancy itself. She also mentioned unintentional weight loss in her last trimester, which, although worrying in itself, did not trigger any cross-sectional imaging at the time. Black stools were also present, although the patient was taking iron supplements. She had no significant medical history, and was not on regular medications apart from over-the-counter vitamins and minerals. A family history was notable for breast and lung cancer in her maternal aunt and grandmother, respectively. She was a teetotaller and a lifelong non-smoker. Examination was consistent with a healthy pregnancy, confirmed on transabdominal ultrasound.

Investigations

Routine work-up revealed deranged liver enzymes (alkaline phosphatase (ALP) 475 U/L, gamma-glutamyl transferase 72 U/L and alanine transaminase 116 U/L), presumed to be secondary to cholestasis of pregnancy, and a microcytic anaemia. These biochemical abnormalities failed to normalise in the puerperium triggering off investigations (figure 1). A transvaginal ultrasound revealed free fluid in the pouch of Douglas, extending to the right adnexae (figures 2 and 3). A CT scan of the abdomen was done due to the presence of free fluid on transvaginal ultrasound, persistent microcytic anaemia, deranged liver profile and lethargy (figure 4). This showed an ill-defined wall thickening in the middle third of the transverse colon. The scan also revealed multiple mesenteric lymph nodes and metastatic lesion of the liver (figure 5).

Figure 1.

Illustration of a trend view for liver enzymes depicting a normal physiological rise for ALP which failed to normalise post partum. ALP, alkaline phosphatase; ALT, alanine transaminase; GGT, gamma-glutamyl transferase.

Figure 2.

Transvaginal ultrasound showing free fluid in the pouch of Douglas.

Figure 3.

Transvaginal ultrasound showing free fluid in the pouch of Douglas.

Figure 4.

CT scan of the abdomen showing a large colonic tumour.

Figure 5.

CT scan of the abdomen showing liver metastases.

An ultrasound-guided biopsy of the liver confirmed metastatic intestinal-type adenocarcinoma. Following a multidisciplinary team meeting, a right hemicolectomy was performed to minimise risk of tumour obstruction or perforation. Histology revealed a pT3N2aM1b transverse colon tumour (TNM eighth edition). Immunohistochemistry revealed loss of the mismatch repair enzymes MLH1 and MSH2. This is consistent with a microsatellite-unstable tumour possibly suggestive of underlying Lynch syndrome.

Differential diagnosis

The high-circulating oestrogen levels in pregnancy are a risk factor for cholelithiasis and approximately 3.5% of pregnancies are complicated by gallstones.² Cholecystitis, cholangitis and acute fatty liver disease are classically painful conditions. An isolated painless cholestatic picture in the third trimester of pregnancy, with a normal bilirubin level, is typically associated with intrahepatic cholestasis of pregnancy.³ This case report highlights that liver masses, although rare, are another important differential diagnosis.

Treatment

The treatment of an extensive stage colonic malignancy consists of systemic chemotherapy with or without immunotherapy. Even though abscopal effect is unlikely the benefit of removing the primary colonic tumour and avoiding a stoma, in line with patient preference, it is significant in terms of minimising the risk of tumour obstruction and perforation. A right hemicolectomy was performed successfully and the patient was then started on oxaliplatin and 5-fluorouracil (5-FU) as per Oxaliplatin Modified de Gramont (FOLFOX) protocol. A port-a-cath was inserted to minimise risk of extravasation, thrombophlebitis and for patient comfort. Dihydropyrimidine dehydrogenase testing was normal. Our patient completed eight cycles of chemotherapy, with an initial biochemical response. Unfortunately, a restaging CT scan showed significant progression in the liver, para-aortic nodes and right iliac bone. In view of the severe pain in her right hemipelvis, she completed 10 sessions of radiotherapy with immediate symptomatic benefit. Subsequently, she was prescribed ipilimumab and nivolumab, as a second-line regimen, with a phenomenal biochemical response following two cycles of immunotherapy (figure 6).

Figure 6.

CA19.9 trend over the past 6 months, coinciding with biochemical progression during oxaliplatin-based chemotherapy and response on introduction of immunotherapy in November 2021.

Discussion

Care for the pregnant and postpartum patient with metastatic colon cancer is intricate on multiple levels including the diagnostic and subsequent management pathways as well as the psychological well-being.

Physiological changes of pregnancy do not alter serological levels of liver enzymes, with the exception of ALP and the tumour marker alpha-fetoprotein. Thus, any derangement requires further assessment. Following a detailed history and targeted examination, a standard serological work-up is recommended. The differential diagnosis can be divided into pregnancy and non-pregnancy liver disease. Various cholestatic liver diseases in childbearing women are unique to pregnancy and directly related to pregnancy-induced changes. However, when managing a patient in pregnancy, pathologies that are not related to pregnancy must also form part of the differential diagnosis. As weight gain is physiological in pregnancy, unintentional weight loss in this case should have been the primary alarm point to investigate the case further, rather than waiting until puerperium.

As explained above, every diagnostic tool has its limitations and risks to mother and child. Given the rarity of metastatic cancer in pregnancy, there is a relative paucity of literature in this regard. What we know is that an isolated rise in ALP does not require additional work-up based on recommendations by the American College of Gastroenterology. The presence of an elevated bilirubin should trigger imaging of the hepatobiliary tract.⁴ It is worth noting our patient’s bilirubin was never elevated at the time of initial presentation. The guideline also recommends the use of ultrasonography as the imaging modality, given the teratogenic risks associated with radiation exposure to CT. If further imaging is necessary, an MRI is recommended, avoiding gadolinium since it crosses the placenta and is excreted into the amniotic fluid.⁵

The gestational period, patient-specific issues and preferences, and stage of malignancy should all be included in the multidisciplinary team discussion. There is generalised consensus that chemotherapy in the first trimester has significant teratogenic effects on the developing fetus and is best avoided. The literature states that 5-FU with or without oxaliplatin during the second and third trimesters was generally safe and well tolerated. Out of 12 patients, there were no stillbirths, and leg length discrepancy in one patient was the only documented congenital malformation.⁶ Given that this was a mismatch repair deficient tumour, use of immunotherapy is not recommended during pregnancy, although no issues have been documented to date in the postpartum period. It is also important to note that termination of pregnancy in the Maltese Islands is currently illegal and cannot be considered even in these difficult circumstances regardless of the term of pregnancy. Further research in this field is therefore necessary to help guide clinicians and patients make a very demanding decision.

The initial decision to proceed with cytotoxic therapy alone was based on the toxicity profile of triple combination regimen and biological agents. This is perhaps conservative given recent trial data showing the superiority of triple combination cytotoxic as first line in metastatic colorectal cancer. With chemotherapy failure, the option of anti-PD-1 and anti-CTLA4 immunotherapy in a microsatellite-unstable tumour was justified and has given our patient an excellent quality of life with a limited toxicity profile to date.

Learning points.

• Liver metastases are a rare but possible cause of elevated liver enzymes in pregnancy.

• Appropriate evaluation is essential prior to attributing symptoms to pregnancy.

• All pregnant women with cholestatic liver derangement should undergo an ultrasound of the liver to exclude biliary obstruction and masses. CT scans, MRI with gadolinium and a Positron emission tomography (PET) scan should be avoided.

Ethics statements

Patient consent for publication

Obtained.